Compounds for the treatment of Alzheimer&#39;s disease

ABSTRACT

The present invention is substituted amines of formula (XV)  
                 
useful in treating Alzheimer&#39;s ease and other similar dise

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to the following provisionalapplications: U.S. provisional application Ser. No. 60/215, 323, filedJun. 30, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds useful in treatment ofAlzheimer's disease and similar diseases.

2. Description of the Related Art

Alzheimer's disease (AD) is a progressive degenerative disease of thebrain primarily associated with aging. Clinical presentation of AD ischaracterized by loss of memory, cognition, reasoning, judgment, andorientation. As the disease progresses, motor, sensory, and linguisticabilities are also affected until there is global impairment of multiplecognitive functions. These cognitive losses occur gradually, buttypically lead to severe impairment and eventual death in the range offour to twelve years.

Alzheimer's disease is characterized by two major pathologicobservations in the brain: neurofibrillary tangles and beta amyloid (orneuritic) plaques, comprised predominantly of an aggregate of a peptidefragment know as A beta. Individuals with AD exhibit characteristicbeta-amyloid deposits in the brain (beta amyloid plaques) and incerebral blood vessels (beta amyloid angiopathy) as well asneurofibrillary tangles. Neurofibrillary tangles occur not only inAlzheimer's disease but also in other dementia-inducing disorders. Onautopsy, large numbers of these lesions are generally found in areas ofthe human brain important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type (HCHWA-D), and other neurogenerative disorders. Beta-amyloidis a defining feature of AD, now believed to be a causative precursor orfactor in the development of disease. Deposition of A beta in areas ofthe brain responsible for cognitive activities is a major factor in thedevelopment of AD. Beta-amyloid plaques are predominantly composed ofamyloid beta peptide (A beta, also sometimes designated betaA4). A betapeptide is derived by proteolysis of the amyloid precursor protein (APP)and is comprised of 39-42 amino acids. Several proteases calledsecretases are involved in the processing of APP.

Cleavage of APP at the N-terminus of the A beta peptide bybeta-secretase and at the C-terminus by one or more gamma-secretasesconstitutes the beta-amyloidogenic pathway, i.e. the pathway by which Abeta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP,a secreted form of APP that does not result in beta-amyloid plaqueformation. This alternate pathway precludes the formation of A betapeptide. A description of the proteolytic processing fragments of APP isfound, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and5,942,400.

An aspartyl protease has been identified as the enzyme responsible forprocessing of APP at the beta-secretase cleavage site. Thebeta-secretase enzyme has been disclosed using varied nomenclature,including BACE, Asp, and Memapsin. See, for example, Sinha et.al., 1999,Nature 402:537-554 (p501) and published PCT application WO00/17369.

Several lines of evidence indicate that progressive cerebral depositionof beta-amyloid peptide (A beta) plays a seminal role in thepathogenesis of AD and can precede cognitive symptoms by years ordecades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A betafrom neuronal cells grown in culture and the presence of A beta incerebrospinal fluid (CSF) of both normal individuals and AD patients hasbeen demonstrated. See, for example, Seubert et al., 1992, Nature359:325-327.

It has been proposed that A beta peptide accumulates as a result of APPprocessing by beta-secretase, thus inhibition of this enzyme's activityis desirable for the treatment of AD. In vivo processing of APP at thebeta-secretase cleavage site is thought to be a rate-limiting step in Abeta production, and is thus a therapeutic target for the treatment ofAD. See for example, Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-19.

BACE1 knockout mice fail to produce A beta, and present a normalphenotype. When crossed with transgenic mice that overexpress APP, theprogeny show reduced amounts of A beta in brain extracts as comparedwith control animals (Luo et.al., 2001 Nature Neuroscience 4:231-232).This evidence further supports the proposal that inhibition ofbeta-secretase activity and reduction of A beta in the brain provides atherapeutic method for the treatment of AD and other beta amyloiddisorders.

Published PCT application WO00/47618 entitled “Beta-Secretase EnzymeCompositions and Methods” identifies the beta-secretase enzyme andmethods of its use. This publication also discloses oligopeptideinhibitors that bind the enzyme's active site and are useful in affinitycolumn purification of the enzyme. In addition, WO00/77030 disclosestetrapeptide inhibitors of beta-secretase activity that are based on astatine molecule.

Various pharmaceutical agents have been proposed for the treatment ofAlzheimer's disease but without any real success. U.S. Pat. No.5,175,281 discloses 21-aminosteroids as being useful for treatingAlzheimer's disease. U.S. Pat. No. 5,502,187 discloses bicyclicheterocyclic amines as being useful for treating Alzheimer's disease.

U.S. Pat. Nos. 4,616,088 and 4,665,193 discloses hydroxyethylaminecompounds as anti-hypertensive agents due to their ability to inhibitrenin.

U.S. Pat. No. 4,636,491 discloses various tetrapeptides which are usefulas renin inhibitors.

U.S. Pat. No. 4,749,792 discloses amino compounds useful as analgesicsbecause of their ability to inhibit an enkephalin-degradingaminopeptidase.

U.S. Pat. No. 5,142,056 discloses peptide derivatives with aC₂-symmetric dihydroxyethylene core as retroviral protease inhibitors.

U.S. Pat. Nos. 5,461,067 and 5,753,652 disclose the synthesis ofretroviral protease inhibitors.

U.S. Pat. Nos. 5,475,138 and 5,631,405 disclose processes and variousintermediates useful in the synthesis of selected protease inhibitors.

U.S. Pat. No. 5,502,061 discloses HIV protease inhibitors containing anunsaturated carbocycle or heterocycle at the C-terminus.

U.S. Pat. No. 5,545,640 discloses compounds which inhibit HIV proteaseactivity.

U.S. Pat. No. 5,516,784 discloses compounds active against retroviruses,including HIV.

U.S. Pat. No. 5,602,175 discloses hydroxyethylamine compounds asretroviral protease inhibitors.

U.S. Pat. No. 5,631,405 discloses a process for the formation ofintermediates useful in the synthesis of selected protease inhibitors.

U.S. Pat. No. 5,733,882 and International Publications WO 93/02057 andWO 93/17003 disclose dipeptide analogs as retroviral proteaseinhibitors.

U.S. Pat. No. 5,760,076 discloses hydroxyethylamino sulfonamidecompounds as retrovirus protease inhibitors.

U.S. Pat. No. 5,807,870 discloses hydroxyethylamine compounds for theinhibition of HIV protease.

U.S. Pat. No. 5,827,891 discloses HIV protease inhibitors.

U.S. Pat. No. 5,830,897 discloses hydroxyethylamino sulfonamidecompounds as retrovirus protease inhibitors.

U.S. Pat. No. 5,831,117 discloses a process and intermediates useful inretroviral protease inhibitor intermediates.

U.S. Pat. No. 5,847,169 discloses a process for preparing aminoepoxidesinvolving the activation of the terminal hydroxyl of an aminodiol.

U.S. Pat. No. 5,849,911 discloses hydroxyethylamine HIV proteaseinhibitors which form hydrazines with one of the amino groups; thisamino group must also be alkylated.

U.S. Pat. No. 5,922,770 discloses peptide derivatives which are usefulin treating disorders resulting from a deficiency in growth hormone.

U.S. Pat. No. 6,013,658 discloses peptide derivatives which are usefulin treating disorders resulting from a deficiency in growth hormone.

U.S. Pat. No. 6,022,872 discloses hydroxyethylamino sulfonyl ureacompounds as HIV protease inhibitors.

U.S. Pat. No. 6,060,476 discloses hydroxyethylamino sulfonamidecompounds as HIV protease inhibitors.

International Publication WO 89/01488 discloses renin inhibitingpeptides with a hydroxyethylene or dihydroxyethylene isostere in the10,11-position of the renin substrate angiotensinogen.

International Publication WO92/00750 discloses retroviral proteaseinhibitors.

International Publication WO 94/04492 discloses hydroxyethylamineintermediates useful for the treatment of retroviral diseases such asHIV. This disclosure also presents epoxides as intermediates for theretroviral inhibitors.

International Publication WO 95/06030 discloses epoxides, chloromethylketones, and alcohols prepared as intermediates for HIV proteaseinhibitors, with a single protecting group on the amine and arylalkylside chain substituted with alkyl, nitro, nitrile, alkoxy, andthioalkoxy; a preferred side chain is 4-fluorophenylmethyl.

International publication WO98/29401 discloses a method for thepreparation of aminoepoxides from aminoaldehydes by which theaminoaldehyde continuously flows into a mixing zone containing an insitu generated halomethyl organometallic reagent.

International Publication WO98/33795 discloses non-peptide inhibitors ofcathepsin D.

International Publication WO98/50342 discloses bis aminomethyl carbonylcompounds as inhibitors of cysteine and serine proteases.

International Publication WO00/056335 discloses non-peptide inhibitorsof aspartyl proteases. These compounds influence processing of theamyloid precursor protein APP.

EP 0 609 625 discloses HIV protease inhibitors with only one noncyclizednitrogen atom.

Bioorganic & Medicinal Chemistry Letters, 5, 721-726 (1995) describesthe synthesis of compounds useful for the inhibition of HIV protease inwhich the C-terminal nitrogen of the hydroxyethylamine compound isincorporated into a ring system such that a piperidine ring, with aamide substituent next to the nitrogen, is formed.

The hydroxyethylamine “nucleus” or isostere, which is present in thecompounds of the present invention has been employed with success in thearea of HIV protease inhibition. Many of these hydroxyethylaminecompounds are known as well as how to make them. See for example, J. Am.Chem. Soc., 93, 288-291 (1993), Tetrahedron Letters, 28(45) 5569-5572(1987), J. Med. Chem., 38(4), 581-584 (1994), Tetrahedron Letters,38(4), 619-620 (1997).

U.S. Pat. No. 5,648,511 discloses a diprotected aralkyl epoxide.

U.S. Pat. Nos. 5,482,947, 5,508,294, 5,510,349, 5,510,388, 5,521,219,5,610,190, 5,639,769, 5,760,064 and 5,965,588 disclose monoprotected(substituted) aralkyl epoxides.

Tetrahedron Lett., 30(40),5425-5428 (1989) discloses a process in whichdoubly protected alpha-amino aldehydes are transformed into thecorresponding aminoalkyl epoxides.

J. Med. Chem., 36, 2300 (1993) discloses an azide substituted benzylepoxide.

Tetrahedron Lett., 38, 3175 (1997) discloses a process for thepreparation of N-BOC protected epoxides from protected amino acidesters.

J. Med. Chem., 35, 2525 (1992) discloses hydroxyethylamine inhibitors ofHIV protease.

U.S. Pat. No. 5,481,011 discloses arylalkyl amino epoxides in which theamino group is protected by a carbamate functionality.

Synlett, 6, 902 (2000) discloses the preparation of alpha-chloroketonesof aminoprotected-(substituted)benzyl esters.

U.S. Pat. No. 5,648,511 discloses a diprotected aralkyl alcohol.

U.S. Pat. Nos. 5,482,947, 5,508,294, 5,510,349, 5,510,388, 5,521,219,5,610,190, 5,639,769, 5,760,064 and 5,965,588 disclose monoprotected(substituted) aralklyl alcohols.

U.S. Pat. Nos. 5,482,947, 5,508,294, 5,510,349, 5,510,388, 5,521,219,5,610,190, 5,639,769, 5,760,064 and 5,965,588 disclose a process forremoving the protecting group of the monoprotected (substituted)aralklyl alcohols to give the free amino alcohol product as the aminesalt.

U.S. Pat. No. 5,648,511 discloses the removal of the amino protectinggroup of a protected amino-alcohol to give a free amino-alcohol.

U.S. Pat. No. 6,150,344 discloses phosphate containing compounds usefulin treating Alzheimer's disease.

EP 652 009 A1 discloses inhibitors of aspartyl protease which inhibitbeta-amyloid peptide production in cell culture and in vivo. Thecompounds which inhibit intracellular beta-amyloid peptide productionare useful in treating Alzheimer's Disease.

WO00/69262 discloses a new beta-secretase and its use in assays toscreen for potential drug candidates against Alzheimer's disease.

WO01/00663 discloses memapsin 2 (human beta-secretase) as well ascatalytically active recombinant enzyme. In addition, a method ofidentifying inhibitors of memapsin 2, as well as two inhibitors aredisclosed. Both inhibitors that are disclosed are peptides.

WO01/00665 discloses inhibitors of memapsin 2 that are useful intreating Alzheimer's disease.

WO01/19797 discloses lactams of the formula C—C—CO—N-lactam-W—X—Y-Zwhich are useful in treating Alzheimer's disease.

EP 98/14450 and J. Med. Chem., 41(18), 3387-3401 (1998) disclose azaanalogs of HIV inhibitors.

At present there are no effective treatments for halting, preventing, orreversing the progression of Alzheimer's disease. Therefore, there is anurgent need for pharmaceutical agents capable of slowing the progressionof Alzheimer's disease and/or preventing it in the first place.

Compounds that are effective inhibitors of beta-secretase, that inhibitbeta-secretase-mediated cleavage of APP, that are effective inhibitorsof A beta production, and/or are effective to reduce amyloid betadeposits or plaques, are needed for the treatment and prevention ofdisease characterized by amyloid beta deposits or plaques, such as AD.

SUMMARY OF THE INVENTION

Disclosed is a substituted amine of formula (XV)

-   where R₁ is:

(I) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₇alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃ alkoxy), —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, and —OC═O NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above,

(II) —CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),

(III) —CH₂—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),

(IV) C₂-C₆ alkenyl with one or two double bonds, optionally substitutedwith one, two or three substituents selected from the group consistingof —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,

(V) C₂-C₆ alkynyl with one or two triple bonds, optionally substitutedwith one, two or three substituents selected from the group consistingof —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,

(VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and whereR_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl,dihydronaphthalyl, or tetralinyl optionally substituted with one, two,three or four of the following substituents on the aryl ring:

-   -   (A) C₁-C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, and C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (B) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (C) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (D) —F, Cl, —Br or —I,    -   (F) —C₁-C₆ alkoxy optionally substituted with one, two or three        of —F,    -   (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        below,    -   (H) —OH,    -   (I) —C≡N,    -   (J) C₃-C₇ cycloalkyl, optionally substituted with one, two or        three substituents selected from the group consisting of —F,        —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)        where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,    -   (K) —CO—(C₁-C₄ alkyl),    -   (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined        above, or    -   (N) —SO₂—(C₁-C₄ alkyl),

(VII) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined above andwhere R_(1-heteroaryl) is selected from the group consisting of:

-   -   pyridinyl,    -   pyrimidinyl,    -   quinolinyl,    -   benzothienyl,    -   indolyl,    -   indolinyl,    -   pryidazinyl,    -   pyrazinyl,    -   isoquinolyl,    -   quinazolinyl,    -   quinoxalinyl,    -   phthalazinyl,    -   imidazolyl,    -   isoxazolyl,    -   pyrazolyl,    -   oxazolyl,    -   thiazolyl,    -   indolizinyl,    -   indazolyl,    -   benzothiazolyl,    -   benzimidazolyl,    -   benzofuranyl,    -   furanyl,    -   thienyl,    -   pyrrolyl,    -   oxadiazolyl,    -   thiadiazolyl,    -   triazolyl,    -   tetrazolyl,    -   oxazolopyridinyl,    -   imidazopyridinyl,    -   isothiazolyl,    -   naphthyridinyl,    -   cinnolinyl,    -   carbazolyl,    -   beta-carbolinyl,    -   isochromanyl,    -   chromanyl,    -   tetrahydroisoquinolinyl,    -   isoindolinyl,    -   isobenzotetrahydrofuranyl,    -   isobenzotetrahydrothienyl,    -   isobenzothienyl,    -   benzoxazolyl,    -   pyridopyridinyl,    -   benzotetrahydrofuranyl,    -   benzotetrahydrothienyl,    -   purinyl,    -   benzodioxolyl,    -   triazinyl,    -   phenoxazinyl,    -   phenothiazinyl,    -   pteridinyl,    -   benzothiazolyl,    -   imidazopyridinyl,    -   imidazothiazolyl,    -   dihydrobenzisoxazinyl,    -   benzisoxazinyl,    -   benzoxazinyl,    -   dihydrobenzisothiazinyl,    -   benzopyranyl,    -   benzothiopyranyl,    -   coumarinyl,    -   isocoumarinyl,    -   chromonyl,    -   chromanonyl,    -   pyridinyl-N-oxide,    -   tetrahydroquinolinyl    -   dihydroquinolinyl    -   dihydroquinolinonyl    -   dihydroisoquinolinonyl    -   dihydrocoumarinyl    -   dihydroisocoumarinyl    -   isoindolinonyl    -   benzodioxanyl    -   benzoxazolinonyl    -   pyrrolyl N-oxide,    -   pyrimidinyl N-oxide,    -   pyridazinyl N-oxide,    -   pyrazinyl N-oxide,    -   quinolinyl N-oxide,    -   indolyl N-oxide,    -   indolinyl N-oxide,    -   isoquinolyl N-oxide,    -   quinazolinyl N-oxide,    -   quinoxalinyl N-oxide,    -   phthalazinyl N-oxide,    -   imidazolyl N-oxide,    -   isoxazolyl N-oxide,    -   oxazolyl N-oxide,    -   thiazolyl N-oxide,    -   indolizinyl N-oxide,    -   indazolyl N-oxide,    -   benzothiazolyl N-oxide,    -   benzimidazolyl N-oxide,    -   pyrrolyl N-oxide,    -   oxadiazolyl N-oxide,    -   thiadiazolyl N-oxide,    -   triazolyl N-oxide,    -   tetrazolyl N-oxide,    -   benzothiopyranyl S-oxide, and    -   benzothiopyranyl S,S-dioxide,

where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by any ringatom of the parent R_(1-heteroaryl) group substituted by hydrogen suchthat the new bond to the R_(1-heteroaryl) group replaces the hydrogenatom and its bond, where heteroaryl is optionally substituted with one,two, three or four of:

-   -   (1) C₁-C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (2) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (3) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (4) —F, Cl, —Br or —I,    -   (6) —C₁-C₆ alkoxy optionally substituted with one, two, or three        of —F,    -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        below,    -   (8) —OH,    -   (9) —C≡N,    -   (10) C₃-C₇ cycloalkyl, optionally substituted with one, two or        three substituents selected from the group consisting of —F,        —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)        where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,    -   (11) —CO—(C₁-C₄ alkyl),    -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above, or    -   (14) —SO₂—(C₁-C₄ alkyl), with the proviso that when n₁ is zero        R_(1-heteroaryl) is not bonded to the carbon chain by nitrogen;        or

(VIII) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is as defined above andR_(1-heterocycle) is selected from the group consisting of:

-   -   morpholinyl,    -   thiomorpholinyl,    -   thiomorpholinyl S-oxide,    -   thiomorpholinyl S,S-dioxide,    -   piperazinyl,    -   homopiperazinyl,    -   pyrrolidinyl,    -   pyrrolinyl,    -   tetrahydropyranyl,    -   piperidinyl,    -   tetrahydrofuranyl,    -   tetrahydrothienyl,    -   homopiperidinyl,    -   homomorpholinyl,    -   homothiomorpholinyl,    -   homothiomorpholinyl S,S-dioxide,    -   oxazolidinonyl,    -   dihydropyrazolyl,    -   dihydropyrrolyl,    -   dihydropyrazinyl,    -   dihydropyridinyl,    -   dihydropyrimidinyl,    -   dihydrofuryl,    -   dihydropyranyl,    -   tetrahydrothienyl S-oxide,    -   tetrahydrothienyl S,S-dioxide, and    -   homothiomorpholinyl S-oxide,

where the R_(1-hetcroycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with one, two, three orfour:

-   -   (1) C₁-C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (2) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (3) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (4) —F, Cl, —Br or —I,    -   (5) C₁-C₆ alkoxy,    -   (6) —C₁-C₆ alkoxy optionally substituted with one, two, or three        —F,    -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        below,    -   (8) —OH,    -   (9) —C≡N,    -   (10) C₃-C₇ cycloalkyl, optionally substituted with one, two or        three substituents selected from the group consisting of —F,        —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)        where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,    -   (11) —CO—(C₁-C₄ alkyl),    -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (14) —SO₂—(C₁-C₄ alkyl), or    -   (15) ═O, with the proviso that when n₁ is zero R_(1-heterocycle)        is not bonded to the carbon chain by nitrogen;

-   where R₂ is:

(I) —H,

(II) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above,

(III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl) whereR_(1-aryl) and R_(1-heteroaryl) are as defined above;

(IV) C₂-C₆ alkenyl with one or two double bonds, optionally substitutedwith one, two or three substituents selected from the group consistingof —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,

(V) C₂-C₆ alkynyl with one or two triple bonds, optionally substitutedwith one, two or three substituents selected from the group consistingof —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, or

(VI) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are —H or C₁-C₆ alkyl;

-   where R₃ is selected from the group consisting of:

(I) —H,

(II) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above,

(III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl) whereR_(1-aryl) and R_(1-heteroaryl) are as defined above

(IV) C₂-C₆ alkenyl with one or two double bonds,

(V) C₂-C₆ alkynyl with one or two triple bonds; or

(VI) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are —H or C₁-C₆ alkyl,

and where R₂ and R₃ are taken together with the carbon to which they areattached to form a carbocycle of three, four, five, six, or seven carbonatoms, optionally where one carbon atom is replaced by a heteroatomselected from the group consisting of —O—, —S—, —SO₂—, and —NR_(N-2)—,where R_(N-2) is as defined below;

-   where R_(N) is:

(I) R_(N-1)—X_(N)— where X_(N) is selected from the group consisting of:

-   -   (A) —CO—,    -   (B) —SO₂—,    -   (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and        are —H and C₁-C₄ alkyl,    -   (D) —CO—(CR′R″)₁₋₆—X_(N-1) where X_(N-1) is selected from the        group consisting of —O—, —S— and —NR′— and where R′ and R″ are        as defined above, and    -   (E) a single bond;

where R_(N-1) is selected from the group consisting of:

-   -   (A) R_(N-aryl) where R_(-aryl) is phenyl, 1-naphthyl,        2-naphthyl, tetralinyl, indanyl,        6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, or dihydronaphthyl        optionally substituted with one, two or three of the following        substituents which can be the same or different and are:        -   (1) C₁-C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃            alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            as defined above,        -   (2) —OH,        -   (3) —NO₂,        -   (4) —F, —Cl, —Br, —I,        -   (5) —CO—OH,        -   (6) —C≡N,        -   (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are the same or different and are selected from the group            consisting of:            -   (a) —H,            -   (b) —C₁-C₆ alkyl optionally substituted with one                substitutent selected from the group consisting of:                -   (i) —OH, and                -   (ii) —NH₂,            -   (c) —C₁-C₆ alkyl optionally substituted with one, two,                or three —F, —Cl, —Br, or —I,            -   (d) —C₃-C₇ cycloalkyl,            -   (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),            -   (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),            -   (g) —C₂-C₆ alkenyl with one or two double bonds,            -   (h) —C₂-C₆ alkynyl with one or two triple bonds,            -   (i) —C₁-C₆ alkyl chain with one double bond and one                triple bond,            -   (R) —R_(1-aryl) where R_(1-aryl) is as defined above,                and            -   (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as                defined above,        -   (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),        -   (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three            double bonds),        -   (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three            triple bonds),        -   (11) —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl),        -   (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined            above,        -   (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is            as defined above,        -   (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle)            is as defined above,        -   (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the            group consisting of morpholinyl, thiomorpholinyl,            piperazinyl, piperidinyl, homomorpholinyl,            homothiomorpholinyl, homothiomorpholinyl S-oxide,            homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl            where each group is optionally substituted with one, two,            three, or four of C₁-C₆ alkyl,        -   (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from            the group consisting of:            -   (a) C₁-C₆ alkyl,            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,            -   (c) C₂-C₆ alkenyl containing one or two double bonds,            -   (d) C₂-C₆ alkynyl containing one or two triple bonds,            -   (e) C₃-C₇ cycloalkyl, and            -   (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl)                is as defined above,        -   (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are as defined above,        -   (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),        -   (19) —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),        -   (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),        -   (21) —(CH₂)₀₋₄N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can            be the same or different and is as defined above,        -   (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5)            can be the same or different and is as defined above,        -   (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the            same or different and is as defined above,        -   (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) and            R_(N-2) can be the same or different and are as defined            above,        -   (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can            be the same or different and are as defined above,        -   (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,        -   (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),        -   (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is            —H or C₁-C₄ alkyl,        -   (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) is as defined            above,        -   (33) —(CH₂)₀₋₄—S—(R_(N-5))2 where R_(N-5) is as defined            above,        -   (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with            one, two, three, four, or five of —F),        -   (35) C₃-C₇ cycloalkyl,        -   (36) C₂-C₆ alkenyl with one or two double bonds optionally            substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b) where R_(1-a)            and R_(1-b) are as defined above,        -   (37) C₂-C₆ alkynyl with one or two triple bonds optionally            substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b) where R_(1-a)            and R_(1-b) are as defined above,        -   (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5)            and R_(N-2) can be the same of different and are as            described above, or        -   (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,    -   (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is selected from        the group consisting of:        -   pyridinyl,        -   pyrimidinyl,        -   quinolinyl,        -   benzothienyl,        -   indolyl,        -   indolinyl,        -   pryidazinyl,        -   pyrazinyl,        -   isoindolyl,        -   isoquinolyl,        -   quinazolinyl,        -   quinoxalinyl,        -   phthalazinyl,        -   imidazolyl,        -   isoxazolyl,        -   pyrazolyl,        -   oxazolyl,        -   thiazolyl,        -   indolizinyl,        -   indazolyl,        -   benzothiazolyl,        -   benzimidazolyl,        -   benzofuranyl,        -   furanyl,        -   thienyl,        -   pyrrolyl,        -   oxadiazolyl,        -   thiadiazolyl,        -   triazolyl,        -   tetrazolyl,        -   oxazolopyridinyl,        -   imidazopyridinyl,        -   isothiazolyl,        -   naphthyridinyl,        -   cinnolinyl,        -   carbazolyl,        -   beta-carbolinyl,        -   isochromanyl,        -   chromanyl,        -   tetrahydroisoquinolinyl,        -   isoindolinyl,        -   isobenzotetrahydrofuranyl,        -   isobenzotetrahydrothienyl,        -   isobenzothienyi,        -   benzoxazolyl,        -   pyridopyridinyl,        -   benzotetrahydrofuranyl,        -   benzotetrahydrothienyl,        -   purinyl,        -   benzodioxolyl,        -   triazinyl,        -   phenoxazinyl,        -   phenothiazinyl,        -   pteridinyl,        -   benzothiazolyl,        -   imidazopyridinyl,        -   imidazothiazolyl,        -   dihydrobenzisoxazinyl,        -   benzisoxazinyl,        -   benzoxazinyl,        -   dihydrobenzisothiazinyl,        -   benzopyranyl,        -   benzothiopyranyl,        -   coumarinyl,        -   isocoumarinyl,        -   chromonyl,        -   chromanonyl,        -   pyridinyl-N-oxide,        -   tetrahydroquinolinyl,        -   dihydroquinolinyl,        -   dihydroquinolinonyl,        -   dihydroisoquinolinonyl,        -   dihydrocoumarinyl,        -   dihydroisocoumarinyl,        -   isoindolinonyl,        -   benzodioxanyl,        -   benzoxazolinonyl,        -   pyrrolyl N-oxide,        -   pyrimidinyl N-oxide,        -   pyridazinyl N-oxide,        -   pyrazinyl N-oxide,        -   quinolinyl N-oxide,        -   indolyl N-oxide,        -   indolinyl N-oxide,        -   isoquinolyl N-oxide,        -   quinazolinyl N-oxide,        -   quinoxalinyl N-oxide,        -   phthalazinyl N-oxide,        -   imidazolyl N-oxide,        -   isoxazolyl N-oxide,        -   oxazolyl N-oxide,        -   thiazolyl N-oxide,        -   indolizinyl N-oxide,        -   indazolyl N-oxide,        -   benzothiazolyl N-oxide,        -   benzimidazolyl N-oxide,        -   pyrrolyl N-oxide,        -   oxadiazolyl N-oxide,        -   thiadiazolyl N-oxide,        -   triazolyl N-oxide,        -   tetrazolyl N-oxide,        -   benzothiopyranyl S-oxide, and        -   benzothiopyranyl S,S-dioxide    -   where the R_(N-heteroaryl) group is bonded by any atom of the        parent R_(N-heteroaryl) group substituted by hydrogen such that        the new bond to the R_(N-heteroaryl) group replaces the hydrogen        atom and its bond, where heteroaryl is optionally substituted        with one, two, three, or four of:        -   (1) C₁-C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃            alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            as defined above,        -   (2) —OH,        -   (3) —NO₂,        -   (4) —F, —Cl, —Br, or —I,        -   (5) —CO—OH,        -   (6) —C≡N,        -   (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are the same or different and are selected from the group            consisting of:            -   (a) —H,            -   (b) —C₁-C₆ alkyl optionally substituted with one                substitutent selected from the group consisting of:                -   (i) —OH, and                -   (ii) —NH₂,            -   (c) —C₁-C₆ alkyl optionally substituted with one, two,                or three —F, —Cl, —Br, —I,            -   (d) —C₃-C₇ cycloalkyl,            -   (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),            -   (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),            -   (g) —C₂-C₆ alkenyl with one or two double bonds,            -   (h) —C₂-C₆ alkynyl with one or two triple bonds,            -   (i) —C₁-C₆ alkyl chain with one double bond and one                triple bond,            -   (j) —R_(1-aryl) where R_(1-aryl) is as defined above,            -   (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as                defined above,        -   (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),        -   (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three            double bonds),        -   (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three            triple bonds),        -   (11) —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl),        -   (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined            above,        -   (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is            as defined above,        -   (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle)            is as defined above,        -   (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the            group consisting of morpholinyl, thiomorpholinyl,            piperazinyl, piperidinyl, homomorpholinyl,            homothiomorpholinyl, homothiomorpholinyl S-oxide,            homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl            where each group is optionally substituted with one, two,            three, or four of C₁-C₆ alkyl,        -   (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from            the group consisting of:            -   (a) C₁-C₆ alkyl,            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,            -   (c) C₂-C₆ alkenyl containing one or two double bonds,            -   (d) C₂-C₆ alkynyl containing one or two triple bonds,            -   (e) C₃-C₇ cycloalkyl, and            -   (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl)                is as defined above,        -   (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are as defined above,        -   (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),        -   (19) —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),        -   (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),        -   (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5)            can be the same or different and is as defined above,        -   (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5)            can be the same or different and is as defined above,        -   (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the            same or different and is as defined above,        -   (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) and            R_(N-2) can be the same or different and are as defined            above,        -   (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can            be the same or different and are as defined above,        -   (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,        -   (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),        -   (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is            —H or C₁-C₄ alkyl,        -   (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) is as defined            above,        -   (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with            one, two, three, four, or five of —F),        -   (35) C₃-C₇ cycloalkyl,        -   (36) C₂-C₆ alkenyl with one or two double bonds optionally            substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b) where R_(1-a)            and R_(1-b) are as defined above,        -   (37) C₂-C₆ alkynyl with one or two triple bonds optionally            substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b) where R_(1-a)            and R_(1-b) are as defined above,            -   (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where                R_(N-5) and R_(N-2) can be the same of different and are                as defined above, or        -   (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,    -   (C) R_(N-aryl)—W—R_(N-aryl), where R_(N-aryl,) and R_(N-aryl)        are as defined above,    -   (D) R_(N-aryl)—W—R_(N-heteroaryl), where R_(N-aryl), and        R_(N-heteroaryl), are as defined above,    -   (E) R_(N-aryl)—W—R_(N-1-heterocycle), wherein        R_(N-1-heterocycle) is the same as R_(1-heterocycle), and        R_(1-heterocycle) is as defined above    -   (F) R_(N-heteroaryl)—W—R_(N-aryl), where R_(N-aryl), and        R_(N-heteroaryl), are as defined above,    -   (G) R_(N-heteroaryl)—W—R_(N-heteroaryl), where R_(N-heteroaryl)        is as defined above,    -   (H) R_(N-heteroaryl)—W—R_(N-1-heterocycle), where        R_(N-heteroaryl), and R_(N-1-heterocycle), are as defined above,    -   (I) R_(N-heterocycle)—W—R_(N-aryl), wherein R_(N-heterocycle) is        the same as R_(1-heterocycle), and R_(1-heterocycle) is as        defined above, and R_(N-aryl) is as defined above,    -   (J) R_(N-heterocycle)—W—R_(N-heteroaryl), where        R_(N-heteroaryl), and R_(N-heterocycle), are as defined above,        and    -   (K) R_(N-heterocycle)—W—R_(N-1-heterocycle), where        R_(N-heterocycle), and R_(N-1-heterocycle), are as defined        above,        -   where W is            -   (1) —(CH₂)₀₋₄—,            -   (2) —O—,            -   (3) —S(O)₀₋₂—,            -   (4) —N(R_(N-5))— where R_(N-5) is as defined above, or            -   (5) —CO—;

(II) —CO—(C₁-C₁₀ alkyl) where alkyl is optionally substituted with onethree substitutents selected from the group consisting of:

-   -   (A) —OH,    -   (B) —C₁-C₆ alkoxy,    -   (C) —C₁-C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or -phenyl,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁-C₈ alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁-C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁-C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or        different and are as defined above,    -   (O) —O—(C₁-C₅ alkyl)-COOH,    -   (P) —O—(C₁-C₆ alkyl optionally substituted with one, two, or        three of —F, —Cl, —Br, —I),    -   (Q) —NH—SO₂—(C₁-C₆ alkyl), and    -   (R) —F, or —Cl,

(III) —CO—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl) where alkyl is optionallysubstituted with one, two, or three of substitutents selected from thegroup consisting of:

-   -   (A) —OH,    -   (B) —C₁-C₆ alkoxy,    -   (C) —C₁-C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or -phenyl,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁-C₈ alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁-C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁-C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or        different and are as defined above,    -   (O) —O—(C₁-C₅ alkyl)-COOH,    -   (P) —O—(C₁-C₆ alkyl optionally substituted with one, two, or        three of —F, —Cl, —Br, or —I),    -   (Q) —NH—SO₂—(C₁-C₆ alkyl), and    -   (R) —F, or —Cl,

(IV) —CO—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl) where alkyl is optionallysubstituted with one, two, or three of substitutents selected from thegroup consisting of:

-   -   (A) —OH,    -   (B) —C₁-C₆ alkoxy,    -   (C) —C₁-C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁-C₈ alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁-C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-4) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁-C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or        different and are as defined above,    -   (O) —O—(C₁-C₅ alkyl)-COOH,    -   (P) —O—(C₁-C₆ alkyl optionally substituted with one, two, or        three of —F, —Cl, —Br, or —I),    -   (Q) —NH—SO₂—(C₁-C₆ alkyl), and    -   (R) —F, or —Cl,

(V) —CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl))where R_(N-aryl) and R_(N-heteroaryl) are as defined above, whereR_(N-10) is selected from the group consisting of:

-   -   (A) —H,    -   (B) C₁-C₆ alkyl,    -   (C) C₃-C₇ cycloalkyl,    -   (D) C₂-C₆ alkenyl with one double bond,    -   (E) C₂-C₆ alkynyl with one triple bond,    -   (F) R_(1-aryl) where R_(1-aryl) is as defined above, and    -   (G) R_(N-heteroaryl) where R_(N-heteroaryl) is as defined above,        or

(VI) —CO—(C₃-C₈ cycloalkyl) where alkyl is optionally substituted withone or two substitutents selected from the group consisting of:

-   -   (A) —(CH₂)₀₋₄—OH,    -   (B) —(CH₂)₀₋₄—C₁-C₆ alkoxy,    -   (C) —(CH₂)₀₋₄—C₁-C₆ thioalkoxy,    -   (D) —(CH₂)₀₋₄—CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or        phenyl,    -   (E) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        the same or different and are as defined above,    -   (F) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —(CH₂)₀₋₄—SO₂—(C₁-C₈ alkyl),    -   (H) —(CH₂)₀₋₄-SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        the same or different and are as defined above,    -   (I) —(CH₂)₀₋₄—NH—CO—(C₁-C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the        same or different and are as defined above,    -   (L) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁-C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or        different and are as defined above,    -   (O) —O—(C₁-C₅ alkyl)-COOH,    -   (P) —O—(C₁-C₆ alkyl optionally substituted with one, two, or        three of —F, —Cl, —Br, or —I),    -   (Q) —NH—SO₂—(C₁-C₆ alkyl), and    -   (R) —F, or —Cl;

-   where R_(A) is:

(I)-C₁-C₁₀ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above, —OC═O NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above, —S(═O)₀₋₂ R_(1-a) whereR_(1-a) is as defined above, —NR_(1-a)C═O NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are as defined above, —C═O NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, and —S(═O)₂ NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are as defined above,

(II) —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can be optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkCyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃,C₁-C₆ alkoxy, —O-phenyl, —CO—OH, —CO—O—(C₁-C₄ alkyl), and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,

(III) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl) where R_(A-x) and R_(A-y) are

-   -   (A) —H,    -   (B) C₁-C₄ alkyl optionally substituted with one or two —OH,    -   (C) C₁-C₄ alkoxy optionally substituted with one, two, or three        of —F,    -   (D) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,    -   (E) C₂-C₆ alkenyl containing one or two double bonds,    -   (F) C₂-C₆ alkynyl containing one or two triple bonds, or    -   (G) phenyl,

and where R_(A-x) and R_(A-y) are taken together with the carbon towhich they are attached to form a carbocycle of three, four, five, sixor seven carbon atoms, optionally where one carbon atom is replaced by aheteroatom selected from the group consisting of —O—, —S—, —SO₂—, and—NR_(N-2)— and R_(A-aryl) is the same as R_(N-aryl),

(IV) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl) where R_(A-heteroaryl) isthe same as R_(N-heteroaryl) and R_(A-x) and R_(A-y) are as definedabove,

(V) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)—R_(A-aryl) where R_(A-aryl),R_(A-x) and R_(A-y) are as defined above,

(VI) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)—R_(A-heteroaryl) where R_(A-aryl),R_(A-heteroaryl), R_(A-x) and R_(A-y) are as defined above,

(VII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)—R_(A-aryl) whereR_(A-heteroaryl), R_(A-aryl), R_(A-x) and R_(A-y) are as defined above,

(VIII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)—R_(A-heteroaryl) whereR_(A-heteroaryl), R_(A-x) and R_(A-y) are as defined above,

(IX) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)—R_(A-heterocycle) whereR_(A-heterocycle) is defined as R_(1-heterocycle), and where R_(A-aryl),R_(A-x) and R_(A-y) are as defined above,

(X) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)—R_(A-heterocycle) whereR_(A-heteroaryl), R_(A-heterocycle), R_(A-x) and R_(A-y) are as definedabove,

(XI) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)—R_(A-aryl) whereR_(A-heterocycle), R_(A-aryl), R_(A-x) and R_(A-y) are as defined above,

(XII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)—R_(A-heteroaryl) whereR_(A-heterocycle), R_(A-heteroaryl), R_(A-x) and R_(A-y) are as definedabove,

(XIII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)—R_(A-heterocycle) whereR_(A-heterocycle), R_(A-x) and R_(A-y) are as defined above,

(XIV) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle) where R_(A-heterocycle),R_(A-x) and R_(A-y) are as defined above,

(XV) —[C(R_(A-1))(R_(A-2))]₁₋₃—CO—N—(R_(A-3))₂ where R_(A-1) and R_(A-2)are the same or different and are selected from the group consisting of:

-   -   (A) —H,    -   (B) —C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,        and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined        above,    -   (C) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (D) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (F) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with one,        two or three substituents selected from the group consisting of        C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆        alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (G) —(C₁-C₄ alkyl)-R_(A′-aryl) where R_(A′-aryl) is as defined        for R_(1-aryl),    -   (H) —(C₁-C₄ alkyl)-R_(A-heteroaryl) where R_(A-heteroaryl) is as        defined above,    -   (I) —(C₁-C₄ alkyl)-R_(A-heterocycle) where R_(A-heterocycle) is        as defined above,    -   (J) —R_(A-heteroaryl) where R_(A-heteroaryl) is as defined        above,    -   (K) —R_(A-heterocycle) where R_(A-heterocycle) is as defined        above,    -   (M) —(CH₂)₁₋₄—R_(A-4)—(CH₂)₀₋₄—R_(A′-aryl) where R_(A-4) is —O—,        —S— or —NR_(A-5)— where R_(A-5) is C₁-C₆ alkyl, and where        R_(A′-aryl) is defined above,    -   (N) —(CH₂)₁₋₄—R_(A-4)—(CH₂)₀₋₄—R_(A-heteroaryl) where R_(A-4)        and R_(A-heteroaryl) are as defined above, and    -   (O) —R_(A′-aryl) where R_(A′-aryl) is as defined above,    -   and where R_(A-3) is the same or different and is:    -   (A) —H,    -   (B) —C₁-C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (C) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (D) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (E) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with one,        two or three substituents selected from the group consisting of        C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆        alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (F) —R_(A′-aryl) where R_(A′-aryl) is as defined above,    -   (G) —R_(A-heteroaryl) where R_(A-heteroaryl) is as defined        above,    -   (H) —R_(A-heterocycle) where R_(A-heterocycle) is as defined        above,

(I) —(C₁-C₄ alkyl)-R_(A′-aryl) where R_(A′-aryl) is as defined above,

-   -   (J) —(C₁-C₄ alkyl)-R_(A-heteroaryl) where R_(A-heteroaryl) is as        defined above,    -   (K) —(C₁-C₄ alkyl)-R_(A-heterocycle) where R_(A-heterocycle) is        as defined above, or

(XVI) —CH(R_(A-aryl))₂ where R_(A-aryl) are the same or different andare as defined above,

(XVII) —CH(R_(A-heteroaryl))₂ where R_(A-heteroaryl) are the same ordifferent and are as defined above,

(XVIII) —CH(R_(A-aryl))(R_(A-heteroaryl)) where R_(A-aryl) andR_(A-heteroaryl) are as defined above,

(XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused toR_(A-aryl), R_(A-heteroaryl), R_(A-heterocycle) where R_(A-aryl) orR_(A-heteroaryl) or R_(A-heterocycle) are as defined above where onecarbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionallyreplaced with NH, NR_(N-5), O, or S(═O)₀₋₂, and where cyclopentyl,cyclohexyl, or -cycloheptyl can be optionally substituted with one ortwo —C₁-C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, ═O, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,

(XX) C₂-C₁₀ alkenyl containing one or two double bonds optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above,

(XXI) C₂-C₁₀ alkynyl containing one or two triple bonds optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above,

(XXI) —(CH₂)₀₋₁—CHR_(A-4)—(CH₂)₀₋₁—R_(A-aryl) where R_(A-aryl) is asdefined above and R_(A-6) is —(CH₂)₀₋₄—OH,

(XXII) —(CH₂)₀₋₁—CHR_(A-6)(CH₂)₀₋₁R_(A-heteroaryl) whereR_(A-heteroaryl) and R_(A-6) is as defined above,

(XXIII) —CH(—R_(A-aryl) or R_(A-heteroaryl))—CO—O(C₁-C₄ alkyl) whereR_(A-aryl) and R_(A-heteroaryl) are as defined above,

(XXIV) —CH(—CH₂—OH)—CH(—OH)-micro-NO₂,

(XXV) (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH,

(XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,

(XXVIII) —H,

(XXIX) —(CH₂)₀₋₄—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and R_(1-b)are as defined above;or

(XXX)

-   -   —C═OC(HR₆)NHR₇, where R₆ and R₇ are as defined below,    -   —C═OR₇, where R₇ is as defined below,    -   —C═OOR₇, where R₇ is as defined below, or    -   —SOOR₇ where R₇ is as defined below,        -   wherein R₆ is:            -   hydrogen,            -   C₁-C₃ alkyl,            -   phenyl,            -   thioalkoxyalkyl,            -   alkyl substituted aryl,            -   cycloalkyl,            -   cycloalkylalkyl,            -   hydroxyalkyl,            -   alkoxyalkyl,            -   aryloxyalkyl,            -   haloalkyl,            -   carboxyalkyl,            -   alkoxycarbonylalkyl,            -   aminoalkyl,            -   (N-protected)aminoalkyl,            -   alkylaminoalkyl,            -   ((N-protected)(alkyl)amino)alkyl,            -   dialkylaminoalkyl,            -   guanidinoalkyl,            -   lower alkenyl,            -   heterocyclic,            -   (heterocyclic)alkyl),            -   arylthioalkyl,            -   arylsulfonyalkyl,            -   (heterocyclic)thioalkyl,            -   (heterocyclic)sulfonylalkyl,            -   (heterocyclic)oxyalkyl,            -   arylalkoxyalkyl,            -   arylthioalkoxyalkyl,            -   arylalkylsulfonylalkyl,            -   (heterocyclic))alkoxyalkyl,            -   (heterocyclic)thioalkoxyalkyl,            -   (heterocyclic)alkylsulfonylalkyl,            -   cycloalkyloxyalkyl,            -   cycloalkylthioalkyl,            -   cycloalkylsulfonylalkyl,            -   cycloalkylalkoxyalkyl,            -   cycloalkylthioalkoxyalkyl,            -   cycloalkylalkylsulfonylalkyl,            -   aminocarbonyl,            -   alkylaminocarbonyl,            -   dialkylaminocarbonyl,            -   aroylalkyl,            -   (heterocyclic)carbonylalkyl,            -   polyhydroxyalkyl,            -   aminocarbonylalkyl,            -   alkylaminocarbonylalkyl,            -   dialkylaminocarbonylalkyl,            -   aryloxyalkyl, or            -   alkylsulfonylalkyl,        -   wherein heterocyclic is pyridyl, thiazolyl, isothiazolyl,            oxazolyl, isoxazolyl, furanyl, thienyl, tetrahydrofuranyl,            tetrahydrothienyl and tetrahydro[2H]pyranyl and wherein the            heterocycle is unsubstituted or substituted with one to            three substituents independently selected from hydroxy,            halo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy,            haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,            COOH, —SO₃H, lower alkenyl or lower alkyl;        -   wherein R₇ is:            -   C₁-C₃ alkyl,            -   phenyl,            -   thioalkoxyalkyl,            -   (aryl)alkyl,            -   cycloalkyl,            -   cycloalkylalkyl,            -   hydroxyalkyl,            -   alkoxyalkyl,            -   aryloxyalkyl,            -   haloalkyl,            -   carboxyalkyl,            -   alkoxycarbonylalkyl,            -   aminoalkyl,            -   (N-protected)aminocalkyl,            -   alkylaminoalkyl,            -   ((N-protected)(alkyl)amino)alkyl,            -   dialkylaminoalkyl,            -   guanidinoalkyl,            -   lower alkenyl,            -   heterocyclic,            -   (heterocyclic)alkyl),            -   arylthioalkyl,            -   arylsulfonyalkyl,            -   (heterocyclic)thioalkyl,            -   (heterocyclic)sulfonylalkyl,            -   (heterocyclic)oxyalkyl,            -   arylalkoxyalkyl,            -   arylthioalkoxyalkyl,            -   arylalkylsulfonylalkyl,            -   (heterocyclic))alkoxyalkyl,            -   (heterocyclic)thioalkoxyalkyl,            -   (heterocyclic)alkylsulfonylalkyl,            -   cycloalkyloxyalkyl,            -   cycloalkylthioalkyl,            -   cycloalkylsulfonylalkyl,            -   cycloalkylalkoxyalkyl,            -   cycloalkylthioalkoxyalkyl,            -   cycloalkylalkylsulfonylalkyl,            -   aminocarbonyl,            -   alkylaminocarbonyl,            -   dialkylaminocarbonyl,            -   aroylalkyl,            -   (heterocyclic)carbonylalkyl,            -   polyhydroxyalkyl,            -   aminocarbonylalkyl,            -   alkylaminocarbonylalkyl,            -   dialkylaminocarbonylalkyl,            -   aryloxyalkyl, or            -   alkylsulfonylalkyl,        -   wherein heterocyclic is pyridyl, thiazolyl, isothiazolyl,            oxazolyl, isoxazolyl, furanyl, thienyl, tetrahydrofuranyl,            tetrahydrothienyl and tetrahydro[2H]pyranyl and wherein the            heterocycle is unsubstituted or substituted with one to            three substituents independently selected from hydroxy,            halo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy,            haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,            COOH, —SO₃H, lower alkenyl or lower alkyl;

-   where X is —N or —O, with the proviso that when X is O, R_(B) is    absent; and

-   when X is N,

R_(B), is:

-   -   (I)-C₁-C₁₀ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,        —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined        above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above,        —NR_(1-a)C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above, —C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)        are as defined above, and —S(═O)₂ NR_(1-a)R_(1-b) where R_(1-a)        and R_(1-b) are as defined above,    -   (II) —(CH₂)₀₋₃—(C₃-C₈)cycloalkyl where cycloalkyl can be        optionally substituted with one, two or three substituents        selected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br,        —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —CO—OH,        —CO—O—(C₁-C₄ alkyl), and —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (III) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl) where R_(B-x) and R_(B-y)        are        -   (A) —H,        -   (B) C₁-C₄ alkyl optionally substituted with one or two —OH,        -   (C) C₁-C₄ alkoxy optionally substituted with one, two, or            three of —F,        -   (D) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,        -   (E) C₂-C₆ alkenyl containing one or two double bonds,        -   (F) C₂-C₆ alkynyl containing one or two triple bonds, or        -   (G) phenyl,        -   and where R_(B-x) and R_(B-y) are taken together with the            carbon to which they are attached to form a carbocycle of            three, four, five, six or seven carbon atoms, optionally            where one carbon atom is replaced by a heteroatom selected            from the group consisting of —O—, —S—, —SO₂—, and —NR_(N-2)            where R_(N-2) is as defined above, and R_(B-aryl) is the            same as R_(N-aryl) and is defined above    -   (IV) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl) where        R_(B-heteroaryl) is the same as R_(N-heteroaryl), R_(B-x), and        R_(B-y) are as defined above,    -   (V) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)—R_(B-aryl) where        R_(B-aryl), R_(B-x), and R_(B-y) are as defined above,    -   (VI) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)—R_(B-heteroaryl) where        R_(B-aryl), R_(B-heteroaryl), R_(B-x) and R_(B-y) are as defined        above,    -   (VII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl)—R_(aryl) where        R_(B-heteroaryl), R_(B-aryl), R_(B-x) and R_(B-y) are as defined        above,    -   (VIII) —(CR_(B-x)R_(B-y))₀₋₄R_(B-heteroaryl)—R_(B-heteroaryl)        where R_(B-heteroaryl), R_(B-x) and R_(B-y) are as defined        above,    -   (IX) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)—R_(B-heterocycle) where        R_(B-heterocycle)is defined as R_(1-heterocycle), and where        R_(B-aryl), R_(B-x) and R_(B-y) are as defined above,    -   (X) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl)—R_(B-heterocycle)        where R_(B-heteroaryl), R_(B-heterocycle), R_(B-x) and R_(B-y)        are as defined above,    -   (XI) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)—R_(B-aryl) where        R_(B-heterocycle), R_(B-aryl), R_(B-x) and R_(B-y) are as        defined above,    -   (XII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)—R_(B-heteroaryl)        where R_(B-heterocycle), R_(B-heteroaryl), R_(B-x) and R_(B-y)        are as defined above,    -   (XIII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)—R_(B-heterocycle)        where R_(B-heterocycle), R_(B-x) and R_(B-y) are as defined        above,    -   (XIV) —(CR_(B-x)R_(B-y))₀₋₄—R_(Heterocycle) where        R_(B-heterocycle), R_(B-x) and R_(B-y) are as defined above,    -   (XV) —[C(R_(B-1))(R_(B-2))]₁₋₃—CO—N—(R_(B-3))₂ where R_(B-1) and        R_(B-2) are the same or different and are selected from the        group consisting of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆            alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (C) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (D) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl),        -   (F) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with            one, two or three substituents selected from the group            consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,            —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where            R_(1-a) and R_(1-b) are as defined above,        -   (G) —(C₁-C₄ alkyl)-R_(B′-aryl) where R_(B′-aryl) is as            defined above for R_(1-aryl),        -   (H) —(C₁-C₄ alkyl)-R_(B-heteroaryl) where R_(B-heteroaryl)            is as defined above,        -   (I) —(C₁-C₄ alkyl)-R_(B-heterocycle) where R_(B-heterocycle)            is as defined above,        -   (J) —R_(B-heteroaryl) where R_(B-heteroaryl) is as defined            above,        -   (K) —R_(B-heterocycle) where R_(B-heterocycle) is as defined            above,        -   (M) —(CH₂)₁₋₄—R_(B-4)—(CH₂)₀₋₄—R_(B′-aryl) where R_(B-4) is            —O—, —S— or —NR_(B-5)— where R_(B-5) is C₁-C₆ alkyl, and            where R_(B′-aryl) is defined above,        -   (N) —(CH₂)₁₋₄—R_(B-4)—(CH₂)₀₋₄—R_(B-heteroaryl) where            R_(B-4) and R_(B-heteroaryl) are as defined above, and        -   (O) —R_(B′-aryl) where R_(B′-aryl) is as defined above,    -   and where R_(B-3) is the same or different and is:        -   (A) —H,        -   (B) —C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆            alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (C) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (D) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (E) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with            one, two or three substituents selected from the group            consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,            —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where            R_(1-a) and R_(1-b) are as defined above,        -   (F) —R_(B′-aryl) where R_(B′-aryl) is as defined above,        -   (G) —R_(B-heteroaryl) where R_(B-heteroaryl) is as defined            above,        -   (H) —R_(B-heterocycle) where R_(B-heterocycle) is as defined            above,    -   (I) —(C₁-C₄ alkyl)-R_(B′-aryl) where R_(B′-aryl) is as defined        above,        -   (J) —(C₁-C₄ alkyl)-R_(B-heteroaryl) where R_(B-heteroaryl)            is as defined above,        -   (K) —(C₁-C₄ alkyl)-R_(B-heterocycle) where R_(B-heterocycle)            is as defined above, or    -   (XVI) —CH(R_(B-aryl))₂ where R_(B-aryl) are the same or        different and are as defined above,    -   (XVII) —CH(R_(B-heteroaryl))₂ where R_(B-heteroaryl) are the        same or different and are as defined above,    -   (XVIII) —CH(R_(B-aryl))(R_(B-heteroaryl)) where R_(B-aryl) and        R_(B-heteroaryl) are as defined above,    -   (XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to        R_(B-aryl) or R_(B-heteroaryl) or R_(B-heterocycle) where        R_(B-aryl) or R_(B-heteroaryl) or R_(B-heterocycle) are as        defined above where one carbon of cyclopentyl, cyclohexyl, or        -cycloheptyl is optionally replaced with NH, NR_(N-5), O, or        S(═O)₀₋₂, and where cyclopentyl, cyclohexyl, or -cycloheptyl can        be optionally substituted with one or two —C₁-C₃ alkyl, —F, —OH,        —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, ═O, or —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (XX) C₂-C₁₀ alkenyl containing one or two double bonds        optionally substituted with one, two or three substituents        selected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br,        —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (XXI) C₂-C₁₀ alkynyl containing one or two triple bonds        optionally substituted with one, two or three substituents        selected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br,        —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (XXI) —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—RB_(B-aryl) where R_(B-aryl)        is as defined above and R_(C-6) is —(CH₂)₀₋₆—OH,    -   (XXII) —CH₂)₀₋₁—CHR_(B-6)—(CH₂)₀₋₁—R_(B-heteroaryl) where        R_(B-heteroaryl) and R_(C-6) is as defined above,    -   (XXIII) —CH(—R_(B-aryl) or R_(B-heteroaryl))—CO—O(C₁-C₄ alkyl)        where R_(B-aryl) and R_(B-heteroaryl) are as defined above,    -   (XXIV) —CH(—CH₂—OH)—CH(—OH)-micro-NO₂,    -   (XXV) (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH,    -   (XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,    -   (XXVIII) —H, or    -   (XXIX) —(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and        R_(1-b) are as defined above,        and pharmaceutically acceptable salts thereof

Disclosed is the use of a compound of formula (XV)

where R₁, R₂, R₃, R_(N), R_(A), R_(B), and X are as defined above forthe compound of formula (XV), and pharmaceutically acceptable saltsthereof for the manufacture of a medicament for use in treating apatient who has, or in preventing a patient from getting, a disease orcondition selected from the group consisting of Alzheimer's disease, forhelping prevent or delay the onset of Alzheimer's disease, for treatingpatients with mild cognitive impairment (MCI) and preventing or delayingthe onset of Alzheimer's disease in those who would progress from MCI toAD, for treating Down's syndrome, for treating humans who haveHereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, fortreating cerebral amyloid angiopathy and preventing its potentialconsequences, i.e. single and recurrent lobar hemorrhages, for treatingother degenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body type ofAlzheimer's disease and who is in need of such treatment.

The present invention provides compounds, compositions, kits, andmethods for inhibiting beta-secretase-mediated cleavage of amyloidprecursor protein (APP). More particularly, the compounds, compositions,and methods of the invention are effective to inhibit the production ofA beta peptide and to treat or prevent any human or veterinary diseaseor condition associated with a pathological form of A beta peptide.

The compounds, compositions, and methods of the invention are useful fortreating humans who have Alzheimer's Disease (AD), for helping preventor delay the onset of AD, for treating patients with mild cognitiveimpairment (MCI), and preventing or delaying the onset of AD in thosepatients who would otherwise be expected to progress from MCI to AD, fortreating Down's syndrome, for treating Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch Type, for treating cerebral beta-amyloidangiopathy and preventing its potential consequences such as single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, fortreating dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, and diffuse Lewy body type AD.

The compounds employed in the methods of the invention possessbeta-secretase inhibitory activity. The inhibitory activities of thecompounds employed in the methods of the invention are readilydemonstrated, for example, using one or more of the assays describedherein or known in the art.

DETAILED DESCRIPTION OF THE INVENTION

The invention includes compounds of formula (XV) that are useful intreating and preventing Alzheimer's disease. The anti-Alzheimer'scompounds of formula (XV) are made by methods well known to thoseskilled in the art from starting compounds known to those skilled in theart. The process chemistry is well known to those skilled in the art.Examples of preparing various compounds of formula (XV) are included incharts A-C. One skilled in the art will appreciate that these are allwell known reactions in organic chemistry. A chemist skilled in the art,knowing the chemical structure of the biologically active compounds offormula (XV) of the invention would be able to prepare them by knownmethods from known starting materials without any additionalinformation. The explanation below therefore is not necessary but isdeemed helpful to those skilled in the art who desire to make compoundsof the invention.

CHART A illustrates a general method of synthesizing compounds of theinvention. The anti-Alzheimer's coumpounds of formula (XV) are preparedby starting with the corresponding epoxide (I). The epoxides (I) arewell known to those skilled in the art or can be readily prepared fromknown compounds by methods well known to those skilled in the art. Thecompounds of formula (XV) of the present invention have at least twoenantiomeric centers which give four enantiomers. The first of theseenantiomeric centers derives from the epoxide starting material (I). Ifa desired enantiomer is preferred, it is preferred to commerciallyobtain or produce the desired enantiomer (S or R) rather than produce anenantiomerically impure mixture and then have to separate out thedesired enantiomer. For the epoxide (1), R₁ is:

(I) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₇alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃ alkoxy), —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, and —OC═O NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above,

(II) —CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),

(III) —CH₂—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),

(IV) C₂-C₆ alkenyl with one or two double bonds, optionally substitutedwith one, two or three substituents selected from the group consistingof —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,

(V) C₂-C₆ alkynyl with one or two triple bonds, optionally substitutedwith one, two or three substituents selected from the group consistingof —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,

(VI) —(CH₂)_(n1—(R) _(1-aryl)) where n₁ is zero or one and whereR_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl,dihydronaphthalyl, or tetralinyl optionally substituted with one, two,three or four of the following substituents on the aryl ring:

-   -   (A) C₁-C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, and C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (B) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (C) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (D) —F, Cl, —Br or —I,    -   (F) —C₁-C₆ alkoxy optionally substituted with one, two or three        of —F,    -   (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        below,    -   (H) —OH,    -   (I) —C≡N,    -   (J) C₃-C₇ cycloalkyl, optionally substituted with one, two or        three substituents selected from the group consisting of —F,        —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)        where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,    -   (K) —CO—(C₁-C₄ alkyl),    -   (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined        above, or    -   (N) —SO₂—(C₁-C₄ alkyl),

(VII) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined above andwhere R_(1-heteroaryl) is selected from the group consisting of:

-   -   pyridinyl,    -   pyrimidinyl,    -   quinolinyl,    -   benzothienyl,    -   indolyl,    -   indolinyl,    -   pryidazinyl,    -   pyrazinyl,    -   isoquinolyl,    -   quinazolinyl,    -   quinoxalinyl,    -   phthalazinyl,    -   imidazolyl,    -   isoxazolyl,    -   pyrazolyl,    -   oxazolyl,    -   thiazolyl,    -   indolizinyl,    -   indazolyl,    -   benzothiazolyl,    -   benzimidazolyl,    -   benzofuranyl,    -   furanyl,    -   thienyl,    -   pyrrolyl,    -   oxadiazolyl,    -   thiadiazolyl,    -   triazolyl,    -   tetrazolyl,    -   oxazolopyridinyl,    -   imidazopyridinyl,    -   isothiazolyl,    -   naphthyridinyl,    -   cinnolinyl,    -   carbazolyl,    -   beta-carbolinyl,    -   isochromanyl,    -   chromanyl,    -   tetrahydroisoquinolinyl,    -   isoindolinyl,    -   isobenzotetrahydrofuranyl,    -   isobenzotetrahydrothienyl,    -   isobenzothienyl,    -   benzoxazolyl,    -   pyridopyridinyl,    -   benzotetrahydrofuranyl,    -   benzotetrahydrothienyl,    -   purinyl,    -   benzodioxolyl,    -   triazinyl,    -   phenoxazinyl,    -   phenothiazinyl,    -   pteridinyl,    -   benzothiazolyl,    -   imidazopyridinyl,    -   imidazothiazolyl,    -   dihydrobenzisoxazinyl,    -   benzisoxazinyl,    -   benzoxazinyl,    -   dihydrobenzisothiazinyl,    -   benzopyranyl,    -   benzothiopyranyl,    -   coumarinyl,    -   isocoumarinyl,    -   chromonyl,    -   chromanonyl,    -   pyridinyl-N-oxide,        -   tetrahydroquinolinyl        -   dihydroquinolinyl        -   dihydroquinolinonyl        -   dihydroisoquinolinonyl        -   dihydrocoumarinyl        -   dihydroisocoumarinyl        -   isoindolinonyl        -   benzodioxanyl        -   benzoxazolinonyl        -   pyrrolyl N-oxide,        -   pyrimidinyl N-oxide,        -   pyridazinyl N-oxide,        -   pyrazinyl N-oxide,        -   quinolinyl N-oxide,        -   indolyl N-oxide,        -   indolinyl N-oxide,        -   isoquinolyl N-oxide,        -   quinazolinyl N-oxide,        -   quinoxalinyl N-oxide,        -   phthalazinyl N-oxide,        -   imidazolyl N-oxide,        -   isoxazolyl N-oxide,        -   oxazolyl N-oxide,        -   thiazolyl N-oxide,        -   indolizinyl N-oxide,        -   indazolyl N-oxide,        -   benzothiazolyl N-oxide,        -   benzimidazolyl N-oxide,        -   pyrrolyl N-oxide,        -   oxadiazolyl N-oxide,        -   thiadiazolyl N-oxide,        -   triazolyl N-oxide,        -   tetrazolyl N-oxide,        -   benzothiopyranyl S-oxide, and        -   benzothiopyranyl S,S-dioxide,

where the R_(1-heteroaryl) group is bonded to —CH₂)_(n1)— by any ringatom of the parent R_(1-heteroaryl) group substituted by hydrogen suchthat the new bond to the R_(1-heteroaryl) group replaces the hydrogenatom and its bond, where heteroaryl is optionally substituted with one,two, three or four of:

-   -   (1) C₁-C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (2) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R₁ are —H or        C₁-C₆ alkyl,    -   (3) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (4) —F, Cl, —Br or —I,    -   (6) —C₁-C₆ alkoxy optionally substituted with one, two, or three        of —F,    -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        below,    -   (8) —OH,    -   (9) —C≡N,    -   (10) C₃-C₇ cycloalkyl, optionally substituted with one, two or        three substituents selected from the group consisting of —F,        —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)        where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,    -   (11) —CO—(C₁-C₄ alkyl),    -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above, or    -   (14) —SO₂—(C₁-C₄ alkyl), with the proviso that when n₁ is zero        R_(1-heteroaryl) is not bonded to the carbon chain by nitrogen;        or

(VIII) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is as defined above andR_(1-heterocycle) is selected from the group consisting of:

-   -   morpholinyl,    -   thiomorpholinyl,    -   thiomorpholinyl S-oxide,    -   thiomorpholinyl S,S-dioxide,    -   piperazinyl,    -   homopiperazinyl,    -   pyrrolidinyl,    -   pyrrolinyl,    -   tetrahydropyranyl,    -   piperidinyl,    -   tetrahydrofuranyl,    -   tetrahydrothienyl,    -   homopiperidinyl,    -   homomorpholinyl,    -   homothiomorpholinyl,    -   homothiomorpholinyl S,S-dioxide,    -   oxazolidinonyl,    -   dihydropyrazolyl,    -   dihydropyrrolyl,    -   dihydropyrazinyl,    -   dihydropyridinyl,    -   dihydropyrimidinyl,    -   dihydrofuryl,    -   dihydropyranyl,    -   tetrahydrothienyl S-oxide,    -   tetrahydrothienyl S,S-dioxide, and    -   homothiomorpholinyl S-oxide,

where the R_(1-heterocycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with one, two, three orfour:

(1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above,

-   -   (2) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (3) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (4) —F, Cl, —Br or —I,    -   (5) C₁-C₆ alkoxy,    -   (6) —C₁-C₆ alkoxy optionally substituted with one, two, or three        —F,    -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        below,    -   (8) —OH,    -   (9) —C≡N,    -   (10) C₃-C₇ cycloalkyl, optionally substituted with one, two or        three substituents selected from the group consisting of —F,        —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)        where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl,    -   (11) —CO—(C₁-C₄ alkyl),    -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (14) —SO₂—(C₁-C₄ alkyl), or    -   (15) ═O, with the proviso that when n₁ is zero R_(1-heterocycle)        is not bonded to the carbon chain by nitrogen.

When R₁ is R_(1-heteroaryl) or R_(1-heterocycle) the bond from theR_(1-heteroaryl) or R_(1-heterocycle) group to the —(CH₂)_(n1)— groupcan be from any ring atom which has an available valence provided thatsuch bond does not result in formation of a charged species or unstablevalence. This means that the R_(1-heteroaryl) or R_(1-heterocycle) groupis bonded to —CH₂)_(n1)—by any ring atom of the parent R_(1-heteroaryl)or R_(1-heterocycle) group which was substituted by hydrogen such thatthe new bond to the R_(1-heteroaryl) or R_(1-heterocycle) group replacesthe hydrogen atom and its bond.

The epoxide (I) also contains the R₂ and R₃ groups. In the epoxide (I),R₂ and R₃ are each independently:

-   -   (I) —H,    -   (II) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or        R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as        defined above    -   (IV) C₂-C₆ alkenyl with one or two double bonds,    -   (V) C₂-C₆ alkynyl with one or two triple bonds; or    -   (VI) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with        one, two or three substituents selected from the group        consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl,    -   and where R₂ and R₃ are taken together with the carbon to which        they are attached to form a carbocycle of three, four, five,        six, or seven carbon atoms, optionally where one carbon atom is        replaced by a heteroatom selected from the group consisting of        —O—, —S—, —SO₂—, and —NR_(N-2)—, where R_(N-2) is as defined        below.

It is preferred that R₂ and R₃ both be —H. If R₂ and R₃ are not thesame, an additional enantiomeric center is added to the molecule.

-   -   Before the synthesis is begun, the free amino group of the        epoxide (1) must be protected with an amino protecting group.        There are a number of methods well known to those skilled in the        art for accomplishing this step. Amino protecting groups are        well known to those skilled in the art. See for example,        “Protecting Groups in Organic Synthesis”, John Wiley and sons,        New York, N.Y., 1981, Chapter 7; “Protecting Groups in Organic        Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2. The        function of the amino protecting group is to protect the free        amino functionality (—NH₂) during subsequent reactions on the        epoxide (I) which would not proceed well, either because the        amino group would react and be functionalized in a way that is        inconsistent with its need to be free for subsequent reactions,        or the free amino group would interfere in the reaction. When        the amino protecting group is no longer needed, it is removed by        methods well known to those skilled in the art. By definition        the amino protecting group must be readily removable as is known        to those skilled in the art by methods well known to those        skilled in the art.

Suitable amino PROTECTING GROUP is selected from the group consisting oft-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, acetyl,trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl,difluoroacetyl, fluoroacetyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluorenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H. It is preferred that theprotecting group be t-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ),it is more preferred that the protecting group be t-butoxycarbonyl. Oneskilled in the art will understand the preferred methods of introducinga t-butoxycarbonyl or benzyloxycarbonyl protecting group and mayadditionally consult T. W. Green and P. G. M. Wuts in “Protective Groupsin Organic Chemistry,” John Wiley and Sons, 1991 for guidance.

Once the epoxide (I) is protected, the synthesis begins with reaction ofa protected epoxide (I) with a hydrazine. The hydrazine provides R_(A),and R_(B) that are present in the final compound (XV). For thehydrazine, R_(A) is:

-   -   (I) —C₁-C₁₀ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,        —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined        above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above,        —NR_(1-a)C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above, —C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)        are as defined above, and —S(═O)₂ NR_(1-a)R_(1-b) where R_(1-a)        and R_(1-b) are as defined above,    -   (II) —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can be        optionally substituted with one, two or three substituents        selected from the group consisting of C₁-C₃ alkCyl, —F, —Cl,        —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —CO—OH,        —CO—O—(C₁-C₄ alkyl), and —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (III) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl) where R_(A-x) and R_(A-y)        are        -   (A) —H,        -   (B) C₁-C₄ alkyl optionally substituted with one or two —OH,        -   (C) C₁-C₄ alkoxy optionally substituted with one, two, or            three of —F,        -   (D) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,        -   (E) C₂-C₆ alkenyl containing one or two double bonds,        -   (F) C₂-C₆ alkynyl contianing one or two triple bonds, or        -   (G) phenyl,    -   and where R_(A-x) and R_(A-y) are taken together with the carbon        to which they are attached to form a carbocycle of three, four,        five, six or seven carbon atoms, optionally where one carbon        atom is replaced by a heteroatom selected from the group        consisting of —O—, —S—, —SO₂—, and —NR_(N-2)— and R_(A-aryl) is        the same as R_(N-aryl),    -   (IV) —(CR_(A-x)R_(A-y))₀₋₄-R_(A-heteroaryl) where        R_(A-heteroaryl) is the same as R_(N-heteroaryl) and R_(A-x) and        R_(A-y) are as defined above,    -   (V) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)—R_(A-aryl) where        R_(A-aryl), R_(A-x) and R_(A-y) are as defined above,    -   (VI) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)—R_(A-heteroaryl) where        R_(A-aryl), R_(A-heteroaryl), R_(A-x) and R_(A-y) are as defined        above,    -   (VII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)—R_(A-aryl) where        R_(A-heteroaryl) R_(A-aryl), R_(A-x) and R_(A-y) are as defined        above,    -   (VIII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)—R_(A-heteroaryl)        where R_(A-heteroaryl), R_(A-x) and R_(A-y) are as defined        above,    -   (IX) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)—R_(A-heterocycle) where        R_(A-heterocycle)is defined as R_(1-heterocycle), and where        R_(A-aryl), R_(A-x) and R_(A-y) are as defined above,    -   (X) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)—R_(A-heterocycle)        where R_(A-heteroaryl), R_(A-heterocycle), R_(A-x) and R_(A-y)        are as defined above,    -   (XI) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)—R_(A-aryl) where        R_(A-heterocycle), R_(A-aryl), R_(A-x) and R_(A-y) are as        defined above,    -   (XII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)—R_(A-heteroaryl)        where R_(A-heterocycle), R_(A-heteroaryl), R_(A-x) and R_(A-y)        are as defined above,    -   (XIII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)—R_(A-heterocycle)        where R_(A-heterocycle), R_(A-x) and R_(A-y) are as defined        above,    -   (XIV) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle) where        R_(A-heterocycle), R_(A-x) and R_(A-y) are as defined above,    -   (XV) —[C(R_(A-1))(R_(A-2))₁₋₃—CO—N—(R_(A-3))₂ where R_(A-1) and        R_(A-2) are the same or different and are selected from the        group consisting of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆            alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (C) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (D) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl),        -   (F) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with            one, two or three substituents selected from the group            consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,            —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where            R_(1-a) and R_(1-b) are as defined above,        -   (G) —(C₁-C₄ alkyl)-R_(A′-aryl) where R_(A′-aryl) is as            defined for R_(1-aryl),        -   (H) —(C₁-C₄ alkyl)-R_(A-heteroaryl) where R_(A-heteroaryl)            is as defined above,        -   (I) —(C₁-C₄ alkyl)-R_(A-heterocycle) where R_(A-heterocycle)            is as defined above,        -   (J) —R_(A-heteroaryl) where R_(A-heteroaryl) is as defined            above,        -   (K) —R_(A-heterocycle) where R_(A-heterocycle) is as defined            above,        -   (M) —(CH₂)₁₋₄—R_(A-4)—(CH₂)₀₋₄-R_(A′-aryl) where R_(A-4) is            —O—, —S— or —NR_(A-5)— where R_(A-5) is C₁-C₆ alkyl, and            where R_(A′-aryl) is defined above,        -   (N) —(CH₂)₁₋₄—R_(A-4)—(CH₂)₀₋₄—R_(A-heteroaryl) where            R_(A-4) and R_(A-heteroaryl) are as defined above, and        -   (O) —R_(A′-aryl) where R_(A′-aryl) is as defined above,

and where R_(A-3) is the same or different and is:

-   -   (A) —H,    -   (B) —C₁-C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (C) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (D) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (E) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with one,        two or three substituents selected from the group consisting of        C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆        alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (F) —R_(A′-aryl) where R_(A′-aryl) is as defined above,    -   (G) —R_(A-heteroaryl) where R_(A-heteroaryl) is as defined        above,    -   (H) —R_(A-heterocycle) where R_(A-heterocycle) is as defined        above,    -   (I) —(C₁-C₄ alkyl)-R_(A′-aryl) where R_(A′-aryl) is as defined        above,    -   (J) —(C₁-C₄ alkyl)-R_(A-heteroaryl) where R_(A-heteroaryl) is as        defined above,    -   (K) —(C₁-C₄ alkyl)-R_(A-heterocycle) where R_(A-heterocycle) is        as defined above, or

(XVI) —CH(R_(A-aryl))₂ where R_(A-aryl) are the same or different andare as defined above,

(XVII) —CH(R_(A-heteroaryl))₂ where R_(A-heteroaryl)are the same ordifferent and are as defined above,

(XVIII) —CH(R_(A-aryl))(R_(A-heteroaryl)) where R_(A-aryl) andR_(A-heteroaryl) are as defined above,

(XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused toR_(A-aryl), R_(A-heteroaryl), R_(A-heterocycle) where R_(A-aryl) orR_(A-heteroaryl) or R_(A-heterocycle) are as defined above where onecarbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionallyreplaced with NH, NR_(N-5), O, or S(═O)₀₋₂, and where cyclopentyl,cyclohexyl, or -cycloheptyl can be optionally substituted with one ortwo —C₁-C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, ═O, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,

(XX) C₂-C₁₀ alkenyl containing one or two double bonds optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above,

(XXI) C₂-C₁₀ alkynyl containing one or two triple bonds optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above,

(XXI) —(CH₂)₀₋₁—CHR_(A-6)—(CH₂)₀₋₁—R_(A-aryl) where R_(A-aryl) is asdefined above and R_(A-6) is —(CH₂)₀₋₆—OH,

(XXI) —(CH₂)₀₋₁—CHR_(A-6)—(CH₂)₀₋₁—R_(A-heteroaryl) whereR_(A-heteroaryl) and R_(A-6) is as defined above,

(XXIII) —CH(—R_(A-aryl) or R_(A-heteroaryl))—CO—O(C₁-C₄ alkyl) whereR_(A-aryl) and R_(A-heteroaryl) are as defined above,

(XXIV) —CH(—CH₂—OH)—CH(—OH)-micro-NO₂,

(XXV) (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH,

(XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,

(XXVIII) —H,

(XXIX) —(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and R_(1-b)are as defined above; or

(XXX)

-   -   —C═OC(HR₆)NHR₇, where R₆ and R₇ are as defined below,    -   —C═OR₇, where R₇ is as defined below,    -   —C═OOR₇, where R₇ is as defined below, or    -   —SOOR₇ where R₇ is as defined below,        -   wherein R₆ is:            -   hydrogen,            -   C₁-C₃ alkyl,            -   phenyl,            -   thioalkoxyalkyl,            -   alkyl substituted aryl,            -   cycloalkyl,            -   cycloalkylalkyl,            -   hydroxyalkyl,            -   alkoxyalkyl,            -   aryloxyalkyl,            -   haloalkyl,            -   carboxyalkyl,            -   alkoxycarbonylalkyl,            -   aminoalkyl,            -   (N-protected)aminoalkyl,            -   alkylaminoalkyl,            -   ((N-protected)(alkyl)amino)alkyl,            -   dialkylaminoalkyl,            -   guanidinoalkyl,            -   lower alkenyl,            -   heterocyclic,            -   (heterocyclic)alkyl),            -   arylthioalkyl,            -   arylsulfonyalkyl,            -   (heterocyclic)thioalkyl,            -   (heterocyclic)sulfonylalkyl,            -   (heterocyclic)oxyalkyl,            -   arylalkoxyalkyl,            -   arylthioalkoxyalkyl,            -   arylalkylsulfonylalkyl,            -   (heterocyclic))alkoxyalkyl,            -   (heterocyclic)thioalkoxyalkyl,            -   (heterocyclic)alkylsulfonylalkyl,            -   cycloalkyloxyalkyl,            -   cycloalkylthioalkyl,            -   cycloalkylsulfonylalkyl,            -   cycloalkylalkoxyalkyl,            -   cycloalkylthioalkoxyalkyl,            -   cycloalkylalkylsulfonylalkyl,            -   aminocarbonyl,            -   alkylaminocarbonyl,            -   dialkylaminocarbonyl,            -   aroylalkyl,            -   (heterocyclic)carbonylalkyl,            -   polyhydroxyalkyl,            -   aminocarbonylalkyl,            -   alkylaminocarbonylalkyl,            -   dialkylaminocarbonylalkyl,            -   aryloxyalkyl, or            -   alkylsulfonylalkyl,        -   wherein heterocyclic is pyridyl, thiazolyl, isothiazolyl,            oxazolyl, isoxazolyl, furanyl, thienyl, tetrahydrofuranyl,            tetrahydrothienyl and tetrahydro[2H]pyranyl and wherein the            heterocycle is unsubstituted or substituted with one to            three substituents independently selected from hydroxy,            halo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy,            haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,            COOH, —SO₃H, lower alkenyl or lower alkyl;        -   wherein R₇ is:            -   C₁-C₃ alkyl,            -   phenyl,            -   thioalkoxyalkyl,            -   (aryl)alkyl,            -   cycloalkyl,            -   cycloalkylalkyl,            -   hydroxyalkyl,            -   alkoxyalkyl,            -   aryloxyalkyl,            -   haloalkyl,            -   carboxyalkyl,            -   alkoxycarbonylalkyl,            -   aminoalkyl,            -   (N-protected)aminocalkyl,            -   alkylaminoalkyl,            -   ((N-protected)(alkyl)amino)alkyl,            -   dialkylaminoalkyl,            -   guanidinoalkyl,            -   lower alkenyl,            -   heterocyclic,            -   (heterocyclic)alkyl),            -   arylthioalkyl,            -   arylsulfonyalkyl,            -   (heterocyclic)thioalkyl,            -   (heterocyclic)sulfonylalkyl,            -   (heterocyclic)oxyalkyl,            -   arylalkoxyalkyl,            -   arylthioalkoxyalkyl,            -   arylalkylsulfonylalkyl,            -   (heterocyclic))alkoxyalkyl,            -   (heterocyclic)thioalkoxyalkyl,            -   (heterocyclic)alkylsulfonylalkyl,            -   cycloalkyloxyalkyl,            -   cycloalkylthioalkyl,            -   cycloalkylsulfonylalkyl,            -   cycloalkylalkoxyalkyl,            -   cycloalkylthioalkoxyalkyl,            -   cycloalkylalkylsulfonylalkyl,            -   aminocarbonyl,            -   alkylaminocarbonyl,            -   dialkylaminocarbonyl,            -   aroylalkyl,            -   (heterocyclic)carbonylalkyl,            -   polyhydroxyalkyl,            -   aminocarbonylalkyl,            -   alkylaminocarbonylalkyl,            -   dialkylaminocarbonylalkyl,            -   aryloxyalkyl, or            -   alkylsulfonylalkyl,        -   wherein heterocyclic is pyridyl, thiazolyl, isothiazolyl,            oxazolyl, isoxazolyl, furanyl, thienyl, tetrahydrofuranyl,            tetrahydrothienyl and tetrahydro[2H]pyranyl and wherein the            heterocycle is unsubstituted or substituted with one to            three substituents independently selected from hydroxy,            halo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy,            haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,            COOH, —SO₃H, lower alkenyl or lower alkyl.

The hydrazine also provides RB in the final compound (XV). For thehydrazine, R_(B) is:

-   -   (I) —C₁-C₁₀ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,        —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined        above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above,        —NR_(1-a)C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above, —C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)        are as defined above, and —S(═O)₂ NR_(1-a)R_(1-b) where R_(1-a)        and R_(1-b) are as defined above,    -   (II) —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can be        optionally substituted with one, two or three substituents        selected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br,        —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —CO—OH,        —CO—O—(C₁-C₄ alkyl), and —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (III) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl) where R_(B-x) and R_(B-y)        are        -   (A) —H,        -   (B) C₁-C₄ alkyl optionally substituted with one or two —OH,        -   (C) C₁-C₄ alkoxy optionally substituted with one, two, or            three of —F,        -   (D) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,        -   (E) C₂-C₆ alkenyl containing one or two double bonds,        -   (F) C₂-C₆ alkynyl contianing one or two triple bonds, or        -   (G) phenyl,        -   and where R_(B-x) and R_(B-y) are taken together with the            carbon to which they are attached to form a carbocycle of            three, four, five, six or seven carbon atoms, optionally            where one carbon atom is replaced by a heteroatom selected            from the group consisting of —O—, —S—, —SO₂—, and —NR_(N-2)            where R_(N-2) is as defined above, and R_(B-aryl) is the            same as R_(N-aryl) and is defined above    -   (IV) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl) where        R_(B-heteroaryl) is the same as R_(N-heteroaryl), R_(B-x), and        R_(B-y) are as defined above,    -   (V) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)—R_(B-aryl) where        R_(B-aryl), R_(B-x), and R_(B-y) are as defined above,    -   (VI) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)—R_(B-heteroaryl) where        R_(B-aryl), R_(B-heteroaryl), R_(B-x) and R_(B-y) are as defined        above,    -   (VII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl)—R_(B-aryl) where        R_(B-heteroaryl), R_(B-aryl), R_(B-x) and R_(B-y) are as defined        above,    -   (VIII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl)—R_(B-heteroaryl)        where R_(B-heteroaryl), R_(B-x) and R_(B-y) are as defined        above,    -   (IX) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)—R_(B-heterocycle) where        R_(B-heterocycle)is defined as R_(1-heterocycle), and where        R_(B-aryl), R_(B-x) and R_(B-y) are as defined above,    -   (X) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl)—R_(B-heterocycle)        where R_(B-heteroaryl), R_(B-heterocycle), R_(B-x) and R_(B-y)        are as defined above,    -   (XI) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)—R_(B-aryl) where        R_(B-heterocycle), R_(B-aryl), R_(B-x) and R_(B-y) are as        defined above,    -   (XII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)—R_(B-heteroaryl)        where R_(B-heterocycle), R_(B-heteroaryl), R_(B-x) and R_(B-y)        are as defined above,    -   (XIII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)—R_(B-heterocycle)        where R_(B-heterocycle), R_(B-x) and R_(B-y) are as defined        above,    -   (XIV) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle) where        R_(B-heterocycle) R_(B-x) and R_(B-y) are as defined above,    -   (XV) —[C(R_(B-1))(R_(B-2))]₁₋₃—CO—N—(R_(B-3))₂ where R_(B-1) and        R_(B-2) are the same or different and are selected from the        group consisting of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆            alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (C) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (D) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl),        -   (F) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with            one, two or three substituents selected from the group            consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,            —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where            R_(1-a) and R₁b are as defined above,        -   (G) —(C₁-C₄ alkyl)-R_(B′-aryl) where R_(B′-aryl) is as            defined above for R_(1-aryl),        -   (H) —(C₁-C₄ alkyl)-R_(B-heteroaryl) where R_(B-heteroaryl)            is as defined above,        -   (I) —(C₁-C₄ alkyl)-R_(B-heterocycle) where R_(B-heterocycle)            is as defined above,        -   (J) —R_(B-heteroaryl) where R_(B-heteroaryl) is as defined            above,        -   (K) —R_(B-heterocycle) where R_(B-heterocycle) is as defined            above,        -   (M) —(CH₂)₁₋₄—R_(B-4)—(CH₂)₀₋₄—R_(B′-aryl) where R_(B-4) is            —O—, —S— or —NR_(B-5)— where R_(B-5) is C₁-C₆ alkyl, and            where R_(B′-aryl) is defined above,        -   (N) —(CH₂)₁₋₄—R_(B-4)—(CH₂)₀₋₄—R_(B-heteroaryl) where            R_(B-4) and R_(B-heteroaryl) are as defined above, and        -   (O) —R_(B′-aryl) where R_(B′-aryl) is as defined above,    -   and where R_(B-3) is the same or different and is:        -   (A) —H,        -   (B) —C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆            alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (C) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (D) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,            —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined            above,        -   (E) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with            one, two or three substituents selected from the group            consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,            —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where            R_(1-a) and R_(1-b) are as defined above,        -   (F) —R_(B′-aryl) where R_(B′-aryl) is as defined above,        -   (G) —R_(B-heteroaryl) where R_(B-heteroaryl) is as defined            above,        -   (H) —R_(B-heterocycle) where R_(B-heterocycle) is as defined            above,        -   (I) —(C₁-C₄ alkyl)-R_(B′-aryl) where R_(B′-aryl) is as            defined above,        -   (J) —(C₁-C₄ alkyl)-R_(B-heteroaryl) where R_(B-heteroaryl)            is as defined above,        -   (K) —(C₁-C₄ alkyl)-R_(B-heterocycle) where R_(B-heterocycle)            is as defined above, or    -   (XVI) —CH(R_(B-aryl))₂ where R_(B-aryl) are the same or        different and are as defined above,    -   (XVII) —CH(R_(B-heteroaryl))₂ where R_(B-heteroaryl) are the        same or different and are as defined above,    -   (XVIII) —CH(R_(B-aryl))(R_(B-heteroaryl)) where R_(B-aryl) and        R_(B-heteroaryl) are as defined above,    -   (XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to        R_(B-aryl) or R_(B-heteroaryl) or R_(B-heterocycle) where        R_(B-aryl) or R_(B-heteroaryl) or R_(B-heterocycle) are as        defined above where one carbon of cyclopentyl, cyclohexyl, or        -cycloheptyl is optionally replaced with NH, NR_(N-5), O, or        S(═O)₀₋₂, and where cyclopentyl, cyclohexyl, or -cycloheptyl can        be optionally substituted with one or two —C₁-C₃ alkyl, —F, —OH,        —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, ═O, or —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (XX) C₂-C₁₀ alkenyl containing one or two double bonds        optionally substituted with one, two or three substituents        selected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br,        —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (XXI) C₂-C₁₀ alkynyl containing one or two triple bonds        optionally substituted with one, two or three substituents        selected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br,        —I, —OH, —SH, —C≡N; —CF₃, C₁-C₆ alkoxy, —O-phenyl, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (XXI) —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)0-1—RB_(B-aryl) where R_(B-aryl)        is as defined above and R_(C-6) is —(CH₂)₀₋₆—OH,    -   (XXII) —CH₂)0-1—CHR_(B-6)—(CH₂)0-1—R_(B-heteroaryl) where        R_(B-heteroaryl)and R_(C-6) is as defined above,    -   (XXIII) —CH(—R_(B-aryl) or R_(B-heteroaryl))—CO—O(C₁-C₄ alkyl)        where R_(B-aryl) and R_(B-heteroaryl) are as defined above,    -   (XXIV) —CH(—CH₂—OH)—CH(—OH)-micro-NO₂,    -   (XXV) (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH,    -   (XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,    -   (XXVIII) —H, or    -   (XXIX) —(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and        R_(1-b) are as defined above.

It is preferred that R_(A) and R_(B) are, independently, C₁-C₈ alkyl,(CH₂)₀₋₃—(C₃-C₇) cycloalkyl, (CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl),(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl),(CR_(A-x)R_(A-y))⁰⁻⁴—R_(A-heterocycle), cyclopentyl or cyclohexyl ringfused to R_(A-aryl) or R_(A-heteroaryl) or R_(A-heterocycle). It is morepreferred that —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl,(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl), (CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl).(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle), or cyclopentyl or -cyclohexylring fused to a R_(A-aryl) or R_(A-heteroaryl) or R_(A-heterocycle). Itis most preferred that R_(B) is (CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl), cyclopentyl or -cyclohexyl ringfused to a R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle).

The epoxide (I) is combined with the hydrazine in hot isopropanolresulting in the selective formation of the hydrazine (II) arising fromalkylation of the unsubstituted nitrogen (M. Nakakata, TetrahedronLetters 1993, 6095-6098). Monoacylation of the hydrazine —NH—NH— withbenzyloxycarbonyl chloride or other acylating agent gives (III) andreduces the reactivity of this group to further acylation irrespectiveof which hydrazine nitrogen the first acyl group becomes attached to (B.Gisin, Helv. Chim. Acta 1970, vol 53, 1030-1043. S. Shinagawa, Chem.Pharm. Bull. 1981, vol 29, 3630-3638). Removal of thetert-butoxycarbonyl protecting group of (III) will provide the freeamine (IV), which is coupled to the compound that provides R_(N). R_(N)is:

-   (I) R_(N-1)—X_(N)— where X_(N) is selected from the group consisting    of:

(A) —CO—,

(B) —SO₂—,

(C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and are —H andC₁-C₄ alkyl,

(D) —CO—(CR′R″)₁₋₆—X_(N-1) where X_(N-1) is selected from the groupconsisting of —O—, —S— and —NR′— and where R′ and R″ are as definedabove, and

(E) a single bond;

-   where R_(N-1) is selected from the group consisting of:

(A) R_(N-aryl) where R_(N-aryl) is phenyl, 1-naphthyl, 2-naphthyl,tetralinyl, indanyl, 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, ordihydronaphthyl optionally substituted with one, two or three of thefollowing substituents which can be the same or different and are:

-   -   (1) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (2) —OH,    -   (3) —NO₂,    -   (4) —F, —Cl, —Br, —I,    -   (5) —CO—OH,    -   (6) —C≡N,    -   (7) —CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        the same or different and are selected from the group consisting        of:        -   (a) —H,        -   (b) —C₁-C₆ alkyl optionally substituted with one            substitutent selected from the group consisting of:            -   (i) —OH, and            -   (ii) —NH₂,        -   (c) —C₁-C₆ alkyl optionally substituted with one, two, or            three —F, —Cl, —Br, or —I,        -   (d) —C₃-C₇ cycloalkyl,        -   (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),        -   (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),        -   (g) —C₂-C₆ alkenyl with one or two double bonds,        -   (h) —C₂-C₆ alkynyl with one or two triple bonds,        -   (i) —C₁-C₆ alkyl chain with one double bond and one triple            bond,        -   (j) —R_(1-aryl) where R_(1-aryl) is as defined above, and        -   (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),    -   (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three double        bonds),    -   (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triple        bonds),    -   (11) —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl),    -   (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined        above,    -   (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above,    -   (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle) is        as defined above,    -   (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the        group consisting of morpholinyl, thiomorpholinyl, piperazinyl,        piperidinyl, homomorpholinyl, homothiomorpholinyl,        homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,        pyrrolinyl and pyrrolidinyl where each group is optionally        substituted with one, two, three, or four of C₁-C₆ alkyl,    -   (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from the        group consisting of:        -   (a) C₁-C₆ alkyl,        -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined            above,        -   (c) C₂-C₆ alkenyl containing one or two double bonds,        -   (d) C₂-C₆ alkynyl containing one or two triple bonds,        -   (e) C₃-C₇ cycloalkyl, and        -   (f) —(CH₂)₀₋₂-(R_(1-heteroaryl)) where R_(1-heteroaryl) is            as defined above,    -   (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        as defined above,    -   (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),    -   (19) —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),    -   (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),    -   (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be        the same or different and is as defined above,    -   (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5) can        be the same or different and is as defined above,    -   (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the same        or different and is as defined above,    -   (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) and        R_(N-2) can be the same or different and are as defined above,    -   (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can be        the same or different and are as defined above,    -   (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,    -   (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),    -   (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is —H        or C₁-C₄ alkyl,    -   (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂ where R_(N-5) is as defined        above,    -   (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ where R_(N-5) is as defined        above,    -   (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5) is as defined above,    -   (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) is as defined        above,    -   (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is as defined above,    -   (34) —(CH₂)₀₋₄—)—(C₁-C₆ alkyl optionally substituted with one,        two, three, four, or five of —F),    -   (35) C₃-C₇ cycloalkyl,    -   (36) C₂-C₆ alkenyl with one or two double bonds optionally        substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,        —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (37) C₂-C₆ alkynyl with one or two triple bonds optionally        substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,        —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) and        R_(N-2) can be the same of different and are as described above,        or    -   (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,

(B) —R_(N-heteroaryl) where R_(N-heteroaryl) is selected from the groupconsisting of:

-   -   pyridinyl,    -   pyrimidinyl,    -   quinolinyl,    -   benzothienyl,    -   indolyl,    -   indolinyl,    -   pryidazinyl,    -   pyrazinyl,    -   isoindolyl,    -   isoquinolyl,    -   quinazolinyl,    -   quinoxalinyl,    -   phthalazinyl,    -   imidazolyl,    -   isoxazolyl,    -   pyrazolyl,    -   oxazolyl,    -   thiazolyl,    -   indolizinyl,    -   indazolyl,    -   benzothiazolyl,    -   benzimidazolyl,    -   benzofuranyl,    -   furanyl,    -   thienyl,    -   pyrrolyl,    -   oxadiazolyl,    -   thiadiazolyl,    -   triazolyl,    -   tetrazolyl,    -   oxazolopyridinyl,    -   imidazopyridinyl,    -   isothiazolyl,    -   naphthyridinyl,    -   cinnolinyl,    -   carbazolyl,    -   beta-carbolinyl,    -   isochromanyl,    -   chromanyl,    -   tetrahydroisoquinolinyl,    -   isoindolinyl,    -   isobenzotetrahydrofuranyl,    -   isobenzotetrahydrothienyl,    -   isobenzothienyl,    -   benzoxazolyl,    -   pyridopyridinyl,    -   benzotetrahydrofuranyl,    -   benzotetrahydrothienyl,    -   purinyl,    -   benzodioxolyl,    -   triazinyl,    -   phenoxazinyl,    -   phenothiazinyl,    -   pteridinyl,    -   benzothiazolyl,    -   imidazopyridinyl,    -   imidazothiazolyl,    -   dihydrobenzisoxazinyl,    -   benzisoxazinyl,    -   benzoxazinyl,    -   dihydrobenzisothiazinyl,    -   benzopyranyl,    -   benzothiopyranyl,    -   coumarinyl,    -   isocoumarinyl,    -   chromonyl,    -   chromanonyl,    -   pyridinyl-N-oxide,    -   tetrahydroquinolinyl,    -   dihydroquinolinyl,    -   dihydroquinolinonyl,    -   dihydroisoquinolinonyl,    -   dihydrocoumarinyl,    -   dihydroisocoumarinyl,    -   isoindolinonyl,    -   benzodioxanyl,    -   benzoxazolinonyl,    -   pyrrolyl N-oxide,    -   pyrimidinyl N-oxide,    -   pyridazinyl N-oxide,    -   pyrazinyl N-oxide,    -   quinolinyl N-oxide,    -   indolyl N-oxide,    -   indolinyl N-oxide,    -   isoquinolyl N-oxide,    -   quinazolinyl N-oxide,    -   quinoxalinyl N-oxide,    -   phthalazinyl N-oxide,    -   imidazolyl N-oxide,    -   isoxazolyl N-oxide,    -   oxazolyl N-oxide,    -   thiazolyl N-oxide,    -   indolizinyl N-oxide,    -   indazolyl N-oxide,    -   benzothiazolyl N-oxide,    -   benzimidazolyl N-oxide,    -   pyrrolyl N-oxide,    -   oxadiazolyl N-oxide,    -   thiadiazolyl N-oxide,    -   triazolyl N-oxide,    -   tetrazolyl N-oxide,    -   benzothiopyranyl S-oxide, and    -   benzothiopyranyl S,S-dioxide

where the R_(N-heteroaryl) group is bonded by any atom of the parentR_(N-heteroaryl) group substituted by hydrogen such that the new bond tothe R_(N-heteroaryl) group replaces the hydrogen atom and its bond,where heteroaryl is optionally substituted with one, two, three, or fourof:

-   -   (1) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (2) —OH,    -   (3) —NO₂,    -   (4) —F, —Cl, —Br, or —I,    -   (5) —CO—OH,    -   (6) —C≡N,    -   (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        the same or different and are selected from the group consisting        of:        -   (a) —H,        -   (b) —C₁-C₆ alkyl optionally substituted with one            substitutent selected from the group consisting of:            -   (i) —OH, and            -   (ii) —NH₂,        -   (c) —C₁-C₆ alkyl optionally substituted with one, two, or            three —F, —Cl, —Br, —I,        -   (d) —C₃-C₇ cycloalkyl,        -   (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),        -   (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),        -   (g) —C₂-C₆ alkenyl with one or two double bonds,        -   (h) —C₂-C₆ alkynyl with one or two triple bonds,        -   (i) —C₁-C₆ alkyl chain with one double bond and one triple            bond,        -   (j) —R_(1-aryl) where R_(1-aryl) is as defined above,        -   (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (8) —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),    -   (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one, two or three double        bonds),    -   (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triple        bonds),    -   (11) —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl),    -   (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined        above,    -   (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above,    -   (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle) is        as defined above,    -   (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the        group consisting of morpholinyl, thiomorpholinyl, piperazinyl,        piperidinyl, homomorpholinyl, homothiomorpholinyl,        homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,        pyrrolinyl and pyrrolidinyl where each group is optionally        substituted with one, two, three, or four of C₁-C₆ alkyl,    -   (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from the        group consisting of:        -   (a) C₁-C₆ alkyl,        -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined            above,        -   (c) C₂-C₆ alkenyl containing one or two double bonds,        -   (d) C₂-C₆ alkynyl containing one or two triple bonds,        -   (e) C₃-C₇ cycloalkyl, and        -   (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl) is            as defined above,    -   (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        as defined above,    -   (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),    -   (19) —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),    -   (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),    -   (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be        the same or different and is as defined above,    -   (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5) can        be the same or different and is as defined above,    -   (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the same        or different and is as defined above,    -   (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) and        R_(N-2) can be the same or different and are as defined above,    -   (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can be        the same or different and are as defined above,    -   (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,    -   (27) —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),    -   (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is —H        or C₁-C₄ alkyl,    -   (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂ where R_(N-5) is as defined        above,    -   (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ where R_(N-5) is as defined        above,    -   (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5) is as defined above,    -   (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) is as defined        above,    -   (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is as defined above,    -   (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with one,        two, three, four, or five of —F),    -   (35) C₃-C₇ cycloalkyl,    -   (36) C₂-C₆ alkenyl with one or two double bonds optionally        substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,        —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (37) C₂-C₆ alkynyl with one or two triple bonds optionally        substituted with C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,        —CF₃, C₁-C₃ alkoxy, or —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above,    -   (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) and        R_(N-2) can be the same of different and are as defined above,        or    -   (39) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,

(C) R_(N-aryl)—W—R_(N-aryl), where R_(N-aryl), and R_(N-aryl) are asdefined above,

(D) R_(N-aryl)—W—R_(N-heteroaryl), where R_(N-aryl), andR_(N-heteroaryl), are as defined above,

(E) R_(N-aryl)—W—R_(N-1-heterocycle), wherein R_(N-1-heterocycle) is thesame as R_(1-heterocycle), and R_(1-heterocycle) is as defined above

(F) R_(N-heteroaryl)—W—R_(N-aryl), where R_(N-aryl), andR_(N-heteroaryl), are as defined above,

(G) R_(N-heteroaryl)—W—R_(N-heteroaryl), where R_(N-heteroaryl) is asdefined above,

(H) R_(N-heteroaryl)—W—R_(N-1-heterocycle), where R_(N-heteroaryl), andR_(N-1-hetercycyle), are as defined above,

(I) R_(N-heterocycle)—W—R_(N-aryl), wherein R_(N-heterocycle) is thesame as R_(1-heterocycle), and R_(1-heterocycle) is as defined above,and R_(N-aryl) is as defined above,

(J) R_(N-heterocycle)—W—R_(N-heteroaryl), where R_(N-heteroaryl), andR_(N-hetercycyle), are as defined above, and

(K) R_(N-heterocycle)—W—R_(N-1-heterocycle), where R_(N-heterocycyle),and R_(N-1-hetercycyle), are as defined above,

-   -   where W is        -   (5) —(CH₂)₀₋₄—,        -   (6) —O—,        -   (7) —S(O)₀₋₂—,        -   (8) —N(R_(N-5))— where R_(N-5) is as defined above, or        -   (5) —CO—;

-   (II) —CO—(C₁-C₁₀ alkyl) where alkyl is optionally substituted with    one three substitutents selected from the group consisting of:

(A) —OH,

(B) —C₁-C₆ alkoxy,

(C) —C₁-C₆ thioalkoxy,

(D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or -phenyl,

(E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

(F) —CO—R_(N-4) where R_(N-4) is as defined above,

(G) —SO₂—(C₁-C₈ alkyl),

(H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

(I) —NH—CO—(C₁-C₆ alkyl),

(J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

(K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or differentand are as defined above,

(L) —R_(N-4) where R_(N-4) is as defined above,

(M) —O—CO—(C₁-C₆ alkyl),

(N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or different andare as defined above,

(O) —O—(C₁-C₅ alkyl)-COOH,

(P) —O—(C₁-C₆ alkyl optionally substitued with one, two, or three of —F,—Cl, —Br, —I),

(Q) —NH—SO₂—(C₁-C₆ alkyl), and

(R) —F, or —Cl,

-   (III) —CO—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl) where alkyl is optionally    substituted with one, two, or three of substitutents selected from    the group consisting of:

(A) —OH,

(B) —C₁-C₆ alkoxy,

(C) —C₁-C₆ thioalkoxy,

(D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or -phenyl,

(E) —O—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

(F) —CO—R_(N-4) where R_(N-4) is as defined above,

(G) —SO₂—(C₁-C₈ alkyl),

(H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

(I) —NH—CO—(C₁-C₆ alkyl),

(J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

(K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or differentand are as defined above,

(L) —R_(N-4) where R_(N-4) is as defined above,

(M) —O—CO—(C₁-C₆ alkyl),

(N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or different andare as defined above,

(O) —O—(C₁-C₅ alkyl)-COOH,

(P) —O—(C₁-C₆ alkyl optionally substitued with one, two, or three of —F,—Cl, —Br, or —I),

(Q) —NH—SO₂—(C₁-C₆ alkyl), and

(R) —F, or —Cl,

-   (IV) —CO—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl) where alkyl is optionally    substituted with one, two, or three of substitutents selected from    the group consisting of:

(A) —OH,

(B) —C₁-C₆ alkoxy,

(C) —C₁-C₆ thioalkoxy,

(D) —CO—O—R_(N-8) where R_(N-8) is as defined above,

(E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

(F) —CO—R_(N-4) where R_(N-4) is as defined above,

(G) —SO₂—(C₁-C₈ alkyl),

(H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

(I) —NH—CO—(C₁-C₆ alkyl),

(J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

(K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or differentand are as defined above,

(L) —R_(N-4) where R_(N-4) is as defined above,

(M) —O—CO—(C₁-C₆ alkyl),

(N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or different andare as defined above,

(O) —O—(C₁-C₅ alkyl)-COOH,

(P) —O—(C₁-C₆ alkyl optionally substitued with one, two, or three of —F,—Cl, —Br, or —I),

(Q) —NH—SO₂—(C₁-C₆ alkyl), and

(R) —F, or —Cl,

-   (V)    —CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl))    where R_(N-aryl) and R_(N-heteroaryl) are as defined above, where    R_(N-10) is selected from the group consisting of:

(A) —H,

(B) C₁-C₆ alkyl,

(C) C₃-C₇ cycloalkyl,

(D) C₂-C₆ alkenyl with one double bond,

(E) C₂-C₆ alkynyl with one triple bond,

(F) R_(1-aryl) where R_(1-aryl) is as defined above, and

(G) R_(N-heteroaryl) where R_(N-heteroaryl) is as defined above, or

-   (VI) —CO—(C₃-C₈ cycloalkyl) where alkyl is optionally substituted    with one or two substitutents selected from the group consisting of:

(A) —(CH₂)₀₋₄—OH,

(B) —(CH₂)₀₋₄—C₁-C₆ alkoxy,

(C) —(CH₂)₀₋₄—C₁-C₆ thioalkoxy,

(D) —(CH₂)₀₋₄—CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or phenyl,

(E) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

(F) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is as defined above,

(G) —(CH₂)₀₋₄—SO₂—(C₁-C₈ alkyl),

(H) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

(I) —(CH₂)₀₋₄—NH—CO—(C₁-C₆ alkyl),

(J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

(K) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

(L) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,

(M) —O—CO—(C₁-C₆ alkyl),

(N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or different andare as defined above,

(O) —O—(C₁-C₅ alkyl)-COOH,

(P) —O—(C₁-C₆ alkyl optionally substitued with one, two, or three of —F,—Cl, —Br, or —I),

(Q) —NH—SO₂—(C₁-C₆ alkyl), and

(R) —F, or —Cl.

The compound that is the source of R_(N) can be coupled with any wellknown coupling agents, an example of which is carbodiimide. Cleavage ofthe acylhydrazine linkage gives the compounds (XV).

CHART A′ gives a more specific example of one method of synthesizingcompounds of the invention (XV). The anti-Alzheimer's coumpounds offormula (XV) are prepared by starting with the corresponding epoxide(I). The epoxides (I) are well known to those skilled in the art or canbe readily prepared from known compounds by methods well known to thoseskilled in the art. The compounds of formula (XV) of the presentinvention have at least two enantiomeric centers which give fourenantiomers. The first of these enantiomeric centers derives from theepoxide starting material (I). If a desired enantiomer is preferred, itis preferred to commercially obtain or produce the desired enantiomer (Sor R) rather than produce an enantiomerically impure mixture and thenhave to separate out the desired enantiomer.

The exemplary synthesis begins by reacting the epoxide (I) with anarmoatic hydraxine in hot isopropanol results in the selective formationof the hydrazines (II) arising from alkylation of the unsubstitutednitrogen (M. Nakakata, Tetrahedron Letters 1993, 6095-6098).Monoacylation of the hydrazine —NH—NH— with benzyloxycarbonyl chlorideor other acylating agent gives (III) and reduces the reactivity of thisgroup to further acylation irrespective of which hydrazine nitrogen thefirst acyl group becomes attached to (B. Gisin, Helv. Chim. Acta 1970,vol 53, 1030-1043. S. Shinagawa, Chem. Pharm. Bull. 1981, vol 29,3630-3638). Removal of the tert-butoxycarbonyl protecting group of (III)will provide the free amine (IV), which is coupled to the isophthalicacid (XIV) using carbodiimide or other well known coupling agents.Cleavage of the acylhydrazine linkage gives a compound of the invention(XV).

CHART B offers another example of a method that can be utilized to makecompounds of the invention. Selective acylation of methylhydrazine onthe substituted nitrogen (D. Butler, J. Medicinal Chemistry 1971, vol.14, 1052-1054) will provide acylhydrazine VI. Treating this hydrazidewith epoxide I in hot isopropanol will provide adduct VII (S. Wang, J.Medicinal Chemistry 1997, vol 40, 937-941. G. Bold, J. MedicinalChemistry 1998, vol 41, 3387-3401). Cleavage of the tert-butoxycarbonylprotecting group and coupling to isophthalic acid (XIV) will provide acompound of the invention (XV).

CHART C offers a general method of making compounds (XV) of theinvention, wherein X is O. A general method of synthesizing compounds(XV) of the invention wherein X is O, begins with a protected epoxide(I). The epoxide (I) again serves to provide R₁, R₂, and R₃ of the finalproduct (XV), the discussion of these compounds offered above appliesequally here. The epoxide is opened with a hydroxylamine having theformula R_(A)—O—NH₂. The hydroxylamine serves both to open the epoxidering and provide R_(A) to the final product (XV). Once the hydroxylaminehas been reacted with the epoxide (I), the adduct (XI) is formed. Adduct(XI) has R₁, R₂, R₃, and R_(A) of the compounds (XV) of the invention.The possible identities of R₁, R₂, R₃, and R_(A), as well as theprotecting group discussed above, apply to adduct (XI) as well. The nextstep in the synthesis of compounds (XV) of the invention, wherein X is Ois cleavage of the protecting group. The protecting groups and methodsof cleaving them discussed above apply similarity to these compounds.After the protecting group has been cleaved from adduct XI, the nextstep involves acylation with the source of R_(N).

CHART C′ offers another more specific illustrative example of one methodof making compounds (XV) of the invention, wherein X is O. Epoxide (I)opening with O-benzylhydroxylamine gives the adduct XI (S. Rosenberg, J.Medicinal Chemistry 1990, vol 33, 1582-1590). Cleavage of thetert-butoxycarbonyl protecting group and acylation with isophthallicacid (as prepared, for example, by the method below) provides the targetcompound XIII.

The preparation of isophthallic acid for use in the above synthesis canbe accomplished for example, by the below synthesis, referring to CHARTD below. Methyl isophthalate (1 equiv, 11.1 mmol) was dissolved in 50:50THF:DMF (20 mL) before the addition of 1,1′carbonyldiimidazole (CDI)(1.2 equiv, 13.3 mmol) at ambient temperature. Upon addition of CDI, acolor change from colorless to yellow, as well as evolution of gas(CO₂), was observed. After gas evolution subsided (approximately oneminute or less), the amine (1.2 equiv, 13.3 mmol) dissolved in DMF anddiisopropylethyl amine (1.2 equiv, 13.3 mmol) was added. After 12 hoursof stirring at ambient temperature, the reaction was partitioned betweensaturated aqueous NH₄Cl and ethyl acetate, and the aqueous layer wasextracted twice more with ethyl acetate. The organic extracts were thenwashed with saturated aqueous solutions of NaHCO₃ and NaCl, and driedover anhydrous MgSO₄ or NaSO₄. Filtration of the drying agent andremoval of solvents in vacuo gave the crude white solid or clear oil.Purification of these compounds if needed was achieved viachromatography on silica gel with 30-40% ethyl acetate in hexanes(80-90% yield).

The methyl isophthalate mono-alkyl or di-alkyl amide (1 equiv, 11.1mmol) was then treated with LiOH.H₂O (3 equiv, 33.3 mmol) in a minimumamount of 1:2:1 THF:MeOH:H₂O and allowed to stir overnight at ambienttemperature. After 12 hours, the solvents were removed in vacuo andsubsequently partitioned between H₂O and ethyl acetate. If emulsionsprohibit separation of the two layers, a small amount of brine was addedto aid in separation. The aqueous layer was extracted once more withethyl acetate (to remove any unreacted starting material). The aqueouslayer was then acidified with concentrated HCl until pH ≦3. Thecloudy-white acidic aqueous solution thus obtained was then extractedthree times with ethyl acetate. These combined organic extracts weredried over anhydrous MgSO₄ or Na₂SO₄. Filtration of the drying agent andremoval of solvents in vacuo gave the crude white solid. The mono- ordi-alkyl amide isophthalate was used crude in the next reaction (90-100%yield).

Compounds of the invention may contain geometric or optical isomers aswell as tautomers. Thus, the invention includes all tautomers and puregeometric isomers, such as the E and Z geometric isomers, as well asmixtures thereof. Furthermore, the invention includes pure enantiomersand diasteriomers as well as mixtures thereof, including racemicmixtures. The individual geometric isomers, enantiomers, ordiastereomers may be prepared or isolated by methods known in the art.

Compounds of the invention with the stereochemistry designated informula XV may be included in mixtures, including racemic mixtures, withother enantiomers, diastereomers, geometric isomers or tautomers.Compounds of the invention with the stereochemistry designated informula XV are typically present in these mixtures in excess of 50percent. Preferably, compounds of the invention with the stereochemistrydesignated in formula XV are present in these mixtures in excess of 80percent. Most preferably, compounds of the invention with thestereochemistry designated in formula XV are present in these mixturesin excess of 90 percent.

The (S,R)-substituted amines (XV) are amines and as such form salts whenreacted with acids. Pharmaceutically acceptable salts are preferred overthe corresponding (S,R)-substituted amines (XV) since they producecompounds which are more water soluble, stable and/or more crystalline.

Pharmaceutically acceptable salts are any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Pharmaceutically acceptable saltsinclude salts of both inorganic and organic acids. The preferredpharmaceutically acceptable salts include salts of the following acidsacetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric,bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic,citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric,gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic,hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic,hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic,malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic,muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic,pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric,phthalic, polygalactouronic, propionic, salicylic, stearic, succinic,succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric,teoclic and toluenesulfonic. For other acceptable salts, see Int. J.Pharm., 33, 201-217 (1986) and J. Pharm. Sci., 66(1), 1, (1977).

The present invention provides compounds, compositions, kits, andmethods for inhibiting beta-secretase enzyme activity and A beta peptideproduction. Inhibition of beta-secretase enzyme activity halts orreduces the production of A beta from APP and reduces or eliminates theformation of beta-amyloid deposits in the brain.

Methods of the Invention

The compounds employed in the methods of the invention, andpharmaceutically acceptable salts thereof, are useful for treatinghumans or animals suffering from a condition characterized by apathological form of beta-amyloid peptide, such as beta-amyloid plaques,and for helping to prevent or delay the onset of such a condition. Forexample, the compounds are useful for treating Alzheimer's disease, forhelping prevent or delay the onset of Alzheimer's disease, for treatingpatients with MCI (mild cognitive impairment) and preventing or delayingthe onset of Alzheimer's disease in those who would progress from MCI toAD, for treating Down's syndrome, for treating humans who haveHereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, fortreating cerebral amyloid angiopathy and preventing its potentialconsequences, i.e. single and recurrent lobal hemorrhages, for treatingother degenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, and diffuse Lewy body typeAlzheimer's disease. The compounds and compositions of the invention areparticularly useful for treating or preventing Alzheimer's disease. Whentreating or preventing these diseases, the compounds employed in themethods of the invention can either be used individually or incombination, as is best for the patient.

As used herein, the term “treating” means that the compounds employed inthe methods of the invention can be used in humans with at least atentative diagnosis of disease. The compounds employed in the methods ofthe invention will delay or slow the progression of the disease therebygiving the individual a more useful life span.

The term “preventing” means that the compounds employed in the method ofthe invention are useful when administered to a patient who has not beendiagnosed as possibly having the disease at the time of administration,but who would normally be expected to develop the disease or be atincreased risk for the disease. The compounds employed in the methods ofthe invention will slow the development of disease symptoms, delay theonset of the disease, or prevent the individual from developing thedisease at all. Preventing also includes administration of the compoundsemployed in the methods of the invention to those individuals thought tobe predisposed to the disease due to age, familial history, genetic orchromosomal abnormalities, and/or due to the presence of one or morebiological markers for the disease, such as a known genetic mutation ofAPP or APP cleavage products in brain tissues or fluids.

In treating or preventing the above diseases, the compounds employed inthe methods of the invention are administered in a therapeuticallyeffective amount. The therapeutically effective amount will varydepending on the particular compound used and the route ofadministration, as is known to those skilled in the art.

In treating a patient displaying any of the diagnosed above conditions aphysician may administer a compound employed in the method of theinvention immediately and continue administration indefinitely, asneeded. In treating patients who are not diagnosed as having Alzheimer'sdisease, but who are believed to be at substantial risk for Alzheimer'sdisease, the physician should preferably start treatment when thepatient first experiences early pre-Alzheimer's symptoms such as, memoryor cognitive problems associated with aging. In addition, there are somepatients who may be determined to be at risk for developing Alzheimer'sthrough the detection of a genetic marker such as APOE4 or otherbiological indicators that are predictive for Alzheimer's disease. Inthese situations, even though the patient does not have symptoms of thedisease, administration of the compounds employed in the methods of theinvention may be started before symptoms appear, and treatment may becontinued indefinitely to prevent or delay the onset of the disease.

Dosage Forms and Amounts

The compounds employed in the methods of the invention can beadministered orally, parenterally, (IV, IM, depo-IM, SQ, and depo SQ),sublingually, intranasally (inhalation), intrathecally, topically, orrectally. Dosage forms known to those of skill in the art are suitablefor delivery of the compounds employed in the methods of the invention.

Compositions are provided that contain therapeutically effective amountsof the compounds employed in the methods of the invention. The compoundsare preferably formulated into suitable pharmaceutical preparations suchas tablets, capsules, or elixirs for oral administration or in sterilesolutions or suspensions for parenteral administration. Typically thecompounds described above are formulated into pharmaceuticalcompositions using techniques and procedures well known in the art.

About 1 to 500 mg of a compound or mixture of compounds employed in themethods of the invention or a physiologically acceptable salt or esteris compounded with a physiologically acceptable vehicle, carrier,excipient, binder, preservative, stabilizer, flavor, etc., in a unitdosage form as called for by accepted pharmaceutical practice. Theamount of active substance in those compositions or preparations is suchthat a suitable dosage in the range indicated is obtained. Thecompositions are preferably formulated in a unit dosage form, eachdosage containing from about 2 to about 100 mg, more preferably about 10to about 30 mg of the active ingredient. The term “unit dosage from”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

To prepare compositions, one or more compounds employed in the methodsof the invention are mixed with a suitable pharmaceutically acceptablecarrier. Upon mixing or addition of the compound(s), the resultingmixture may be a solution, suspension, emulsion, or the like. Liposomalsuspensions may also be suitable as pharmaceutically acceptablecarriers. These may be prepared according to methods known to thoseskilled in the art. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for lessening or ameliorating atleast one symptom of the disease, disorder, or condition treated and maybe empirically determined.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the active materials can also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, or have another action.The compounds may be formulated as the sole pharmaceutically activeingredient in the composition or may be combined with other activeingredients.

Where the compounds exhibit insufficient solubility, methods forsolubilizing may be used. Such methods are known and include, but arenot limited to, using cosolvents such as dimethylsulfoxide (DMSO), usingsurfactants such as Tween®, and dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as salts or prodrugs mayalso be used in formulating effective pharmaceutical compositions.

The concentration of the compound is effective for delivery of an amountupon administration that lessens or ameliorates at least one symptom ofthe disorder for which the compound is administered. Typically, thecompositions are formulated for single dosage administration.

The compounds employed in the methods of the invention may be preparedwith carriers that protect them against rapid elimination from the body,such as time-release formulations or coatings. Such carriers includecontrolled release formulations, such as, but not limited to,microencapsulated delivery systems. The active compound is included inthe pharmaceutically acceptable carrier in an amount sufficient to exerta therapeutically useful effect in the absence of undesirable sideeffects on the patient treated. The therapeutically effectiveconcentration may be determined empirically by testing the compounds inknown in vitro and in vivo model systems for the treated disorder.

The compounds and compositions of the invention can be enclosed inmultiple or single dose containers. The enclosed compounds andcompositions can be provided in kits, for example, including componentparts that can be assembled for use. For example, a compound inhibitorin lyophilized form and a suitable diluent may be provided as separatedcomponents for combination prior to use. A kit may include a compoundinhibitor and a second therapeutic agent for co-administration. Theinhibitor and second therapeutic agent may be provided as separatecomponent parts. A kit may include a plurality of containers, eachcontainer holding one or more unit dose of the compound employed in themethod of the invention. The containers are preferably adapted for thedesired mode of administration, including, but not limited to tablets,gel capsules, sustained-release capsules, and the like for oraladministration; depot products, pre-filled syringes, ampoules, vials,and the like for parenteral administration; and patches, medipads,creams, and the like for topical administration.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the active compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

If oral administration is desired, the compound should be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules, or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches, and the like can contain any ofthe following ingredients or compounds of a similar nature: a bindersuch as, but not limited to, gum tragacanth, acacia, corn starch, orgelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a gildant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials, whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings, and flavors.

The active materials can also be mixed with other active materials thatdo not impair the desired action, or with materials that supplement thedesired action.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent such as water for injection, saline solution, fixed oil,a naturally occurring vegetable oil such as sesame oil, coconut oil,peanut oil, cottonseed oil, and the like, or a synthetic fatty vehiclesuch as ethyl oleate, and the like, polyethylene glycol, glycerine,propylene glycol, or other synthetic solvent; antimicrobial agents suchas benzyl alcohol and methyl parabens; antioxidants such as ascorbicacid and sodium bisulfite; chelating agents such asethylenediaminetetraacetic acid (EDTA); buffers such as acetates,citrates, and phosphates; and agents for the adjustment of tonicity suchas sodium chloride and dextrose. Parenteral preparations can be enclosedin ampoules, disposable syringes, or multiple dose vials made of glass,plastic, or other suitable material. Buffers, preservatives,antioxidants, and the like can be incorporated as required.

Where administered intravenously, suitable carriers includephysiological saline, phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents such as glucose,polyethylene glycol, polypropyleneglycol, and mixtures thereof.Liposomal suspensions including tissue-targeted liposomes may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known for example, as described in U.S. Pat. No.4,522,811.

The active compounds may be prepared with carriers that protect thecompound against rapid elimination from the body, such as time-releaseformulations or coatings. Such carriers include controlled releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid, and the like.Methods for preparation of such formulations are known to those skilledin the art.

The compounds employed in the methods of the invention can beadministered orally, parenterally (IV, IM, depo-IM, SQ, and depo-SQ),sublingually, intranasally (inhalation), intrathecally, topically, orrectally. Dosage forms known to those skilled in the art are suitablefor delivery of the compounds employed in the methods of the invention.

Compounds employed in the methods of the invention may be administeredenterally or parenterally. When administered orally, compounds employedin the methods of the invention can be administered in usual dosageforms for oral administration as is well known to those skilled in theart. These dosage forms include the usual solid unit dosage forms oftablets and capsules as well as liquid dosage forms such as solutions,suspensions, and elixirs. When the solid dosage forms are used, it ispreferred that they be of the sustained release type so that thecompounds employed in the methods of the invention need to beadministered only once or twice daily.

The oral dosage forms are administered to the patient 1, 2, 3, or 4times daily. It is preferred that the compounds employed in the methodsof the invention be administered either three or fewer times, morepreferably once or twice daily. Hence, it is preferred that thecompounds employed in the methods of the invention be administered inoral dosage form. It is preferred that whatever oral dosage form isused, that it be designed so as to protect the compounds employed in themethods of the invention from the acidic environment of the stomach.Enteric coated tablets are well known to those skilled in the art. Inaddition, capsules filled with small spheres each coated to protect fromthe acidic stomach, are also well known to those skilled in the art.

When administered orally, an administered amount therapeuticallyeffective to inhibit beta-secretase activity, to inhibit A betaproduction, to inhibit A beta deposition, or to treat or prevent AD isfrom about 0.1 mg/day to about 1,000 mg/day. It is preferred that theoral dosage is from about 1 mg/day to about 100 mg/day. It is morepreferred that the oral dosage is from about 5 mg/day to about 50mg/day. It is understood that while a patient may be started at onedose, that dose may be varied over time as the patient's conditionchanges.

Compounds employed in the methods of the invention may also beadvantageously delivered in a nano crystal dispersion formulation.Preparation of such formulations is described, for example, in U.S. Pat.No. 5,145,684. Nano crystalline dispersions of HIV protease inhibitorsand their method of use are described in U.S. Pat. No. 6,045,829. Thenano crystalline formulations typically afford greater bioavailabilityof drug compounds.

The compounds employed in the methods of the invention can beadministered parenterally, for example, by IV, IM, depo-IM, SC, ordepo-SC. When administered parenterally, a therapeutically effectiveamount of about 0.5 to about 100 mg/day, preferably from about 5 toabout 50 mg daily should be delivered. When a depot formulation is usedfor injection once a month or once every two weeks, the dose should beabout 0.5 mg/day to about 50 mg/day, or a monthly dose of from about 15mg to about 1,500 mg. In part because of the forgetfulness of thepatients with Alzheimer's disease, it is preferred that the parenteraldosage form be a depo formulation.

The compounds employed in the methods of the invention can beadministered sublingually. When given sublingually, the compoundsemployed in the methods of the invention should be given one to fourtimes daily in the amounts described above for IM administration.

The compounds employed in the methods of the invention can beadministered intranasally. When given by this route, the appropriatedosage forms are a nasal spray or dry powder, as is known to thoseskilled in the art. The dosage of the compounds employed in the methodsof the invention for intranasal administration is the amount describedabove for IM administration.

The compounds employed in the methods of the invention can beadministered intrathecally. When given by this route the appropriatedosage form can be a parenteral dosage form as is known to those skilledin the art. The dosage of the compounds employed in the methods of theinvention for intrathecal administration is the amount described abovefor IM administration.

The compounds employed in the methods of the invention can beadministered topically. When given by this route, the appropriate dosageform is a cream, ointment, or patch. Because of the amount of thecompounds employed in the methods of the invention to be administered,the patch is preferred. When administered topically, the dosage is fromabout 0.5 mg/day to about 200 mg/day. Because the amount that can bedelivered by a patch is limited, two or more patches may be used. Thenumber and size of the patch is not important, what is important is thata therapeutically effective amount of the compounds employed in themethods of the invention be delivered as is known to those skilled inthe art. The compounds employed in the methods of the invention can beadministered rectally by suppository as is known to those skilled in theart. When administered by suppository, the therapeutically effectiveamount is from about 0.5 mg to about 500 mg.

The compounds employed in the methods of the invention can beadministered by implants as is known to those skilled in the art. Whenadministering a compound employed in the method of the invention byimplant, the therapeutically effective amount is the amount describedabove for depot administration.

The invention here is the new compounds employed in the methods of theinvention and new methods of using the compounds employed in the methodsof the invention. Given a particular compound employed in the method ofthe invention and a desired dosage form, one skilled in the art wouldknow how to prepare and administer the appropriate dosage form.

The compounds employed in the methods of the invention are used in thesame manner, by the same routes of administration, using the samepharmaceutical dosage forms, and at the same dosing schedule asdescribed above, for preventing disease or treating patients with MCI(mild cognitive impairment) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating or preventing Down's syndrome, for treating humans who haveHereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, fortreating cerebral amyloid angiopathy and preventing its potentialconsequences, i.e. single and recurrent lobar hemorrhages, for treatingother degenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, and diffuse Lewy body typeof Alzheimer's disease.

The compounds employed in the methods of the invention can be used incombination, with each other or with other therapeutic agents orapproaches used to treat or prevent the conditions listed above. Suchagents or approaches include: acetylcholine esterase inhibitors such astacrine (tetrahydroaminoacridine, marketed as COGNEX®), donepezilhydrochloride, (marketed as Aricept® and rivastigmine (marketed asExelon®); gamma-secretase inhibitors; anti-inflammatory agents such ascyclooxygenase II inhibitors; anti-oxidants such as Vitamin E andginkolides; immunological approaches, such as, for example, immunizationwith A beta peptide or administration of anti-A beta peptide antibodies;statins; and direct or indirect neurotropic agents such asCerebrolysin®, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and otherneurotropic agents of the future.

It should be apparent to one skilled in the art that the exact dosageand frequency of administration will depend on the particular compoundsemployed in the methods of the invention administered, the particularcondition being treated, the severity of the condition being treated,the age, weight, general physical condition of the particular patient,and other medication the individual may be taking as is well known toadministering physicians who are skilled in this art.

Inhibition of APP Cleavage

The compounds employed in the methods of the invention inhibit cleavageof APP between Met595 and Asp596 numbered for the APP695 isoform, or amutant thereof, or at a corresponding site of a different isoform, suchas APP751 or APP770, or a mutant thereof (sometimes referred to as the“beta secretase site”). While not wishing to be bound by a particulartheory, inhibition of beta-secretase activity is thought to inhibitproduction of beta amyloid peptide (A beta). Inhibitory activity isdemonstrated in one of a variety of inhibition assays, whereby cleavageof an APP substrate in the presence of a beta-secretase enzyme isanalyzed in the presence of the inhibitory compound, under conditionsnormally sufficient to result in cleavage at the beta-secretase cleavagesite. Reduction of APP cleavage at the beta-secretase cleavage sitecompared with an untreated or inactive control is correlated withinhibitory activity. Assay systems that can be used to demonstrateefficacy of the compound inhibitors of the invention are known.Representative assay systems are described, for example, in U.S. Pat.Nos. 5,942,400, 5,744,346, as well as in the Examples below.

The enzymatic activity of beta-secretase and the production of A betacan be analyzed in vitro or in vivo, using natural, mutated, and/orsynthetic APP substrates, natural, mutated, and/or synthetic enzyme, andthe test compound. The analysis may involve primary or secondary cellsexpressing native, mutant, and/or synthetic APP and enzyme, animalmodels expressing native APP and enzyme, or may utilize transgenicanimal models expressing the substrate and enzyme. Detection ofenzymatic activity can be by analysis of one or more of the cleavageproducts, for example, by immunoassay, fluorometric or chromogenicassay, HPLC, or other means of detection. Inhibitory compounds aredetermined as those having the ability to decrease the amount ofbeta-secretase cleavage product produced in comparison to a control,where beta-secretase mediated cleavage in the reaction system isobserved and measured in the absence of inhibitory compounds.

Beta-Secretase

Various forms of beta-secretase enzyme are known, and are available anduseful for assay of enzyme activity and inhibition of enzyme activity.These include native, recombinant, and synthetic forms of the enzyme.Human beta-secretase is known as Beta Site APP Cleaving Enzyme (BACE),Asp2, and memapsin 2, and has been characterized, for example, in U.S.Pat. No. 5,744,346 and published PCT patent applications WO98/22597,WO00/03819, WO01/23533, and WO00/17369, as well as in literaturepublications (Hussain et al., 1999, Mol. Cell. Neurosci. 14:419-427;Vassar et al., 1999, Science 286:735-741; Yan et al., 1999, Nature402:533-537; Sinha et al., 1999, Nature 40:537-540; and Lin et al.,2000, PNAS USA 97:1456-1460). Synthetic forms of the enzyme have alsobeen described (WO98/22597 and WO00/17369). Beta-secretase can beextracted and purified from human brain tissue and can be produced incells, for example mammalian cells expressing recombinant enzyme.

Useful inhibitory compounds are effective to inhibit 50% ofbeta-secretase enzymatic activity at a concentration of less than 50micromolar, preferably at a concentration of 10 micromolar or less, morepreferably 1 micromolar or less, and most preferably 10 nanomolar orless.

APP Substrate

Assays that demonstrate inhibition of beta-secretase-mediated cleavageof APP can utilize any of the known forms of APP, including the 695amino acid “normal” isotype described by Kang et al., 1987, Nature325:733-6, the 770 amino acid isotype described by Kitaguchi et. al.,1981, Nature 331:530-532, and variants such as the Swedish Mutation(KM670-INL) (APP-SW), the London Mutation (V7176F), and others. See, forexample, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature Genet.1:233-234, for a review of known variant mutations. Additional usefulsubstrates include the dibasic amino acid modification, APP-KKdisclosed, for example, in WO 00/17369, fragments of APP, and syntheticpeptides containing the beta-secretase cleavage site, wild type (WT) ormutated form, e.g., SW, as described, for example, in U.S. Pat. No.5,942,400 and WO00/03819.

The APP substrate contains the beta-secretase cleavage site of APP(KM-DA or NL-DA) for example, a complete APP peptide or variant, an APPfragment, a recombinant or synthetic APP, or a fusion peptide.Preferably, the fusion peptide includes the beta-secretase cleavage sitefused to a peptide having a moiety useful for enzymatic assay, forexample, having isolation and/or detection properties. A useful moietymay be an antigenic epitope for antibody binding, a label or otherdetection moiety, a binding substrate, and the like.

Antibodies

Products characteristic of APP cleavage can be measured by immunoassayusing various antibodies, as described, for example, in Pirttila et al.,1999, Neuro. Lett. 249:21-4, and in U.S. Pat. No. 5,612,486. Usefulantibodies to detect A beta include, for example, the monoclonalantibody 6E10 (Senetek, St. Louis, Mo.) that specifically recognizes anepitope on amino acids 1-16 of the A beta peptide; antibodies 162 and164 (New York State Institute for Basic Research, Staten Island, N.Y.)that are specific for human A beta 1-40 and 1-42, respectively; andantibodies that recognize the junction region of beta-amyloid peptide,the site between residues 16 and 17, as described in U.S. Pat. No.5,593,846. Antibodies raised against a synthetic peptide of residues 591to 596 of APP and SW192 antibody raised against 590-596 of the Swedishmutation are also useful in immunoassay of APP and its cleavageproducts, as described in U.S. Pat. Nos. 5,604,102 and 5,721,130.

Assay Systems

Assays for determining APP cleavage at the beta-secretase cleavage siteare well known in the art. Exemplary assays, are described, for example,in U.S. Pat. Nos. 5,744,346 and 5,942,400, and described in the Examplesbelow.

Cell Free Assays

Exemplary assays that can be used to demonstrate the inhibitory activityof the compounds employed in the methods of the invention are described,for example, in WO00/17369, WO 00/03819, and U.S. Pat. Nos.5,942,400 and5,744,346. Such assays can be performed in cell-free incubations or incellular incubations using cells expressing a beta-secretase and an APPsubstrate having a beta-secretase cleavage site.

An APP substrate containing the beta-secretase cleavage site of APP, forexample, a complete APP or variant, an APP fragment, or a recombinant orsynthetic APP substrate containing the amino acid sequence: KM-DA orNL-DA, is incubated in the presence of beta-secretase enzyme, a fragmentthereof, or a synthetic or recombinant polypeptide variant havingbeta-secretase activity and effective to cleave the beta-secretasecleavage site of APP, under incubation conditions suitable for thecleavage activity of the enzyme. Suitable substrates optionally includederivatives that may be fusion proteins or peptides that contain thesubstrate peptide and a modification useful to facilitate thepurification or detection of the peptide or its beta-secretase cleavageproducts. Useful modifications include the insertion of a knownantigenic epitope for antibody binding; the linking of a label ordetectable moiety, the linking of a binding substrate, and the like.

Suitable incubation conditions for a cell-free in vitro assay include,for example: approximately 200 nanomolar to 10 micromolar substrate,approximately 10 to 200 picomolar enzyme, and approximately 0.1nanomolar to 10 micromolar inhibitor compound, in aqueous solution, atan approximate pH of 4-7, at approximately 37 degrees C., for a timeperiod of approximately 10 minutes to 3 hours. These incubationconditions are exemplary only, and can be varied as required for theparticular assay components and/or desired measurement system.Optimization of the incubation conditions for the particular assaycomponents should account for the specific beta-secretase enzyme usedand its pH optimum, any additional enzymes and/or markers that might beused in the assay, and the like. Such optimization is routine and willnot require undue experimentation.

One useful assay utilizes a fusion peptide having maltose bindingprotein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBPportion is captured on an assay substrate by anti-MBP capture antibody.Incubation of the captured fusion protein in the presence ofbeta-secretase results in cleavage of the substrate at thebeta-secretase cleavage site. Analysis of the cleavage activity can be,for example, by immunoassay of cleavage products. One such immunoassaydetects a unique epitope exposed at the carboxy terminus of the cleavedfusion protein, for example, using the antibody SW192. This assay isdescribed, for example, in U.S. Pat. No. 5,942,400.

Cellular Assay

Numerous cell-based assays can be used to analyze beta-secretaseactivity and/or processing of APP to release A beta. Contact of an APPsubstrate with a beta-secretase enzyme within the cell and in thepresence or absence of a compound inhibitor of the invention can be usedto demonstrate beta-secretase inhibitory activity of the compound.Preferably, assay in the presence of a useful inhibitory compoundprovides at least about 30%, most preferably at least about 50%inhibition of the enzymatic activity, as compared with a non-inhibitedcontrol.

In one embodiment, cells that naturally express beta-secretase are used.Alternatively, cells are modified to express a recombinantbeta-secretase or synthetic variant enzyme as discussed above. The APPsubstrate may be added to the culture medium and is preferably expressedin the cells. Cells that naturally express APP, variant or mutant formsof APP, or cells transformed to express an isoform of APP, mutant orvariant APP, recombinant or synthetic APP, APP fragment, or syntheticAPP peptide or fusion protein containing the beta-secretase APP cleavagesite can be used, provided that the expressed APP is permitted tocontact the enzyme and enzymatic cleavage activity can be analyzed.

Human cell lines that normally process A beta from APP provide a usefulmeans to assay inhibitory activities of the compounds employed in themethods of the invention. Production and release of A beta and/or othercleavage products into the culture medium can be measured, for exampleby immunoassay, such as Western blot or enzyme-linked immunoassay (EIA)such as by ELISA.

Cells expressing an APP substrate and an active beta-secretase can beincubated in the presence of a compound inhibitor to demonstrateinhibition of enzymatic activity as compared with a control. Activity ofbeta-secretase can be measured by analysis of one or more cleavageproducts of the APP substrate. For example, inhibition of beta-secretaseactivity against the substrate APP would be expected to decrease releaseof specific beta-secretase induced APP cleavage products such as A beta.

Although both neural and non-neural cells process and release A beta,levels of endogenous beta-secretase activity are low and often difficultto detect by EIA. The use of cell types known to have enhancedbeta-secretase activity, enhanced processing of APP to A beta, and/orenhanced production of A beta are therefore preferred. For example,transfection of cells with the Swedish Mutant form of APP (APP-SW); withAPP-KK, or with APP-SW-KK provides cells having enhanced beta-secretaseactivity and producing amounts of A beta that can be readily measured.

In such assays, for example, the cells expressing APP and beta-secretaseare incubated in a culture medium under conditions suitable forbeta-secretase enzymatic activity at its cleavage site on the APPsubstrate. On exposure of the cells to the compound inhibitor, theamount of A beta released into the medium and/or the amount of CTF99fragments of APP in the cell lysates is reduced as compared with thecontrol. The cleavage products of APP can be analyzed, for example, byimmune reactions with specific antibodies, as discussed above.

Preferred cells for analysis of beta-secretase activity include primaryhuman neuronal cells, primary transgenic animal neuronal cells where thetransgene is APP, and other cells such as those of a stable 293 cellline expressing APP, for example, APP-SW.

In vivo Assays: Animal Models

Various animal models can be used to analyze beta-secretase activity and/or processing of APP to release A beta, as described above. Forexample, transgenic animals expressing APP substrate and beta-secretaseenzyme can be used to demonstrate inhibitory activity of the compoundsemployed in the methods of the invention. Certain transgenic animalmodels have been described, for example, in U.S. Pat. Nos. 5,877,399;5,612,486; 5,387,742; 5,720,936; 5,850,003; 5,877,015, and 5,811,633,and in Ganes et al., 1995, Nature 373:523. Preferred are animals thatexhibit characteristics associated with the pathophysiology of AD.Administration of the compound inhibitors of the invention to thetransgenic mice described herein provides an alternative method fordemonstrating the inhibitory activity of the compounds. Administrationof the compounds in a pharmaceutically effective carrier and via anadministrative route that reaches the target tissue in an appropriatetherapeutic amount is also preferred.

Inhibition of beta-secretase mediated cleavage of APP at thebeta-secretase cleavage site and of A beta release can be analyzed inthese animals by measure of cleavage fragments in the animal's bodyfluids such as cerebral fluid or tissues. Analysis of brain tissues forA beta deposits or plaques is preferred.

On contacting an APP substrate with a beta-secretase enzyme in thepresence of an inhibitory compound employed in the method of theinvention and under conditions sufficient to permit enzymatic mediatedcleavage of APP and/or release of A beta from the substrate, thecompounds employed in the methods of the invention are effective toreduce beta-secretase-mediated cleavage of APP at the beta-secretasecleavage site and/or effective to reduce released amounts of A beta.Where such contacting is the administration of the inhibitory compoundsemployed in the methods of the invention to an animal model, forexample, as described above, the compounds are effective to reduce Abeta deposition in brain tissues of the animal, and to reduce the numberand/or size of beta amyloid plaques. Where such administration is to ahuman subject, the compounds are effective to inhibit or slow theprogression of disease characterized by enhanced amounts of A beta, toslow the progression of AD in the, and/or to prevent onset ordevelopment of AD in a patient at risk for the disease.

Unless defined otherwise, all scientific and technical terms used hereinhave the same meaning as commonly understood by one of skill in the artto which this invention belongs. All patents and publications referredto herein are hereby incorporated by reference for all purposes.

DEFINITIONS AND CONVENTIONS

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES

The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R_(i)” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃—C(=Z₁)H. Groups R_(i) and R_(j)would represent monovalent variable substituents if attached to theformula CH₃—CH₂—C(R_(i))(R_(j))H₂. When chemical formulas are drawn in alinear fashion, such as those above, variable substituents contained inparentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parenthesis. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₆ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R₆” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “—” in general representsa bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃represents a 2-substituted-1-methoxypropane compound. In a similarfashion, the symbol “═” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “≡” represents a triple bond, e.g.,HC≡C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments canbe represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridine can be represented in linear fashion byN*═C(CH₃)—CH═CCl—CH═C*H with the convention that the atoms marked withan asterisk (*) are bonded to each other resulting in the formation of aring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinylcan be represented by —N*—(CH₂)₂—N(C₂H₅)—CH₂—C*H₂.

A rigid cyclic (ring) structure for any compounds herein defines anorientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, —C(X₁)(X₂)— the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha configurationand is identified by a broken, dashed or dotted line attachment to thecarbon atom, i.e., by the symbol “ - - -” or “ . . . ”. Thecorresponding substituent attached “above” (X₂) the other (X₁) isidentified as being in the beta configuration and is indicated by anunbroken line attachment to the carbon atom.

When a variable substituent is bivalent, the valences may be takentogether or separately or both in the definition of the variable. Forexample, a variable R_(i) attached to a carbon atom as —C(═R_(i))— mightbe bivalent and be defined as oxo or keto (thus forming a carbonyl group(—CO—) or as two separately attached monovalent variable substituentsalpha-R_(i-j) and beta-R_(i-k). When a bivalent variable, R_(i), isdefined to consist of two monovalent variable substituents, theconvention used to define the bivalent variable is of the form“alpha-R_(i-j):beta-R_(i-k)” or some variant thereof. In such a caseboth alpha-R_(i-j) and beta-R_(i-k) are attached to the carbon atom togive —C(alpha-R_(i-j))(beta-R_(i-k))—. For example, when the bivalentvariable R₆, —C(═R₆)— is defined to consist of two monovalent variablesubstituents, the two monovalent variable substituents arealpha-R₆₋₁:beta-R₆₋₂, . . . alpha-R₆₋₉:beta-R₆₋₁₀, etc, giving—C(alpha-R₆₋₁)(beta-R₆₋₂)—, . . . —C(alpha-R₆₋₉)(beta-R₆₋₁₀)—, etc.Likewise, for the bivalent variable R₁₁, —C(═R₁₁)—, two monovalentvariable substituents are alpha-R₁₁₋₁:beta-R₁₁₋₂. For a ring substituentfor which separate alpha and beta orientations do not exist (e.g. due tothe presence of a carbon carbon double bond in the ring), and for asubstituent bonded to a carbon atom which is not part of a ring theabove convention is still used, but the alpha and beta designations areomitted.

Just as a bivalent variable may be defined as two separate monovalentvariable substituents, two separate monovalent variable substituents maybe defined to be taken together to form a bivalent variable. Forexample, in the formula —C₁(R_(i))H—C₂(R_(j))H— (C₁ and C₂ definearbitrarily a first and second carbon atom, respectively) R_(i) andR_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (—O—) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group —X—Y—, thenthe orientation of the entity is such that C₁ in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation “. . . R_(i) and R_(j) are taken together to form —CH₂—CH₂—O—CO— . . . ”means a lactone in which the carbonyl is bonded to C₂. However, whendesignated “ . . . R_(j) and R_(i) are taken together to form—CO—O—CH₂—CH₂— the convention means a lactone in which the carbonyl isbonded to C₁.

The carbon atom content of variable substituents is indicated in one oftwo ways. The first method uses a prefix to the entire name of thevariable such as “C₁-C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂-C₄ alkoxycarbonyl describes a group CH₃—(CH₂)_(n)-0-CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)-C_(j)” designation in parentheses and placing it immediately(no intervening space) before the portion of the definition beingdefined. By this optional convention (C₁-C₃)alkoxycarbonyl has the samemeaning as C₂-C₄ alkoxy-carbonyl because the “C₁-C₃” refers only to thecarbon atom content of the alkoxy group. Similarly while both C₂-C₆alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groupscontaining from 2 to 6 carbon atoms, the two definitions differ sincethe former definition allows either the alkoxy or alkyl portion alone tocontain 4 or 5 carbon atoms while the latter definition limits either ofthese groups to 3 carbon atoms.

When the claims contain a fairly complex (cyclic) substituent, at theend of the phrase naming/designating that particular substituent will bea notation in (parentheses) which will correspond to the samename/designation in one of the CHARTS which will also set forth thechemical structural formula of that particular substituent.

II. DEFINITIONS

All temperatures are in degrees Celsius.

TLC refers to thin-layer chromatography.

psi refers to pounds/in².

HPLC refers to high pressure liquid chromatography.

THF refers to tetrahydrofuran.

DMF refers to dimethylformamide.

EDC refers to ethyl-1-(3-dimethylaminopropyl)carbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

HOBt refers to 1-hydroxy benzotriazole hydrate.

NMM refers to N-methylmorpholine.

NBS refers to N-bromosuccinimide.

TEA refers to triethylamine.

BOC refers to 1,1-dimethylethoxy carbonyl or t-butoxycarbonyl,—CO—O—C(CH₃)₃.

CBZ refers to benzyloxycarbonyl, —CO—O—CH₂-φ.

FMOC refers to 9-fluorenylmethyl carbonate.

TFA refers to trifluoracetic acid, CF₃—COOH.

CDI refers to 1,1′-carbonyldiimidazole.

Saline refers to an aqueous saturated sodium chloride solution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (d) downfield from TMS.

IR refers to infrared spectroscopy.

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. MH⁺ refers to the positive ion of a parent plus a hydrogen atom.EI refers to electron impact. CI refers to chemical ionization. FABrefers to fast atom bombardment.

HRMS refers to high resolution mass spectrometry.

Ether refers to diethyl ether.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate.

TBDMSCl refers to t-butyldimethylsilyl chloride.

TBDMSOTf refers to t-butyldimethylsilyl trifluorosulfonic acid ester.

Trisomy 21 refers to Down's Syndrome.

The following terms are used (in EXAMPLEs 321 and above) for the amideforming agent (IX):

“PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO-phenyl-CO—OH where the attachmentto the—phenyl-ring is 1,3- ;

“5-Me-PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO—(CH₃—) phenyl —CO—OH where theattachment to the—phenyl-ring is 1,3- for the carbonyl groups and 5- forthe methyl group;

“3,5-pyridinyl” refers to (CH₃—CH₂—CH₂—)₂N—CO-(pyridinyl)-CO—OH wherethe attachment to the—pyridinyl-ring is 3,5- for the carbonyl groups;

“—SO₂—” refers to (CH₃—CH₂—CH₂—)₂CH—SO₂— phenyl —CO—OH where theattachment to the—phenyl-ring is 1,3- ;

“5-OMe-PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO—(CH₃—O—) phenyl —CO—OH wherethe attachment to the—phenyl-ring is 1,3- for the carbonyl groups and 5-for the methoxy group;

“5-Cl—PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO—(Cl-)phenyl-CO—OH where theattachment to the—phenyl-ring is 1,3- for the carbonyl groups and 5- forthe chlorine atom;

“5-F—PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO—(F-)phenyl-CO—OH where theattachment to the—phenyl-ring is 1,3- for the carbonyl groups and 5- forthe fluorine atom;

“thienyl” refers to (CH₃—CH₂—CH₂—)₂N—CO-thienyl-CO—OH where theattachment to the thiophene ring is −2,5;

“2,4-pyridinyl” refers to (CH₃—CH₂—CH₂—)₂N—CO-(pyridinyl)-CO—OH wherethe attachment to the—pyridinyl-ring is 2,4- for the carbonyl groups;

“4,6-pyrimidinyl” refers to(CH₃—CH₂—CH₂—)₂N—CO-(pyrimidinyl-)phenyl-CO—OH where the attachment tothe—pyrimidiny-1 ring is 4,6- for the carbonyl groups;

“morpholinyl” refers to morpholinyl-CO-phenyl-CO—OH where the attachmentto the—phenyl-ring is 1,3 for the carbonyl groups.

APP, amyloid precursor protein, is defined as any APP polypeptide,including APP variants, mutations, and isoforms, for example, asdisclosed in U.S. Pat. No. 5,766,846.

A beta, amyloid beta peptide, is defined as any peptide resulting frombeta-secretase mediated cleavage of APP, including peptides of 39, 40,41, 42, and 43 amino acids, and extending from the beta-secretasecleavage site to amino acids 39, 40, 41, 42, or 43.

Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl protease thatmediates cleavage of APP at the amino-terminal edge of A beta. Humanbeta-secretase is described, for example, in WO00/17369.

A therapeutically effective amount is defined as an amount effective toreduce or lessen at least one symptom of the disease being treated or toreduce or delay onset of one or more clinical markers or symptoms of thedisease.

The present invention provides compounds, compositions, and methods forinhibiting beta-secretase enzyme activity and A beta peptide production.Inhibition of beta-secretase enzyme activity halts or reduces theproduction of A beta from APP and reduces or eliminates the formation ofbeta-amyloid deposits in the brain.

CHEMICAL EXAMPLES

Exemplary Compounds of the Invention

Examples of compounds that are within the invention include but are notlimited to those depicted below.

Example 1N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(N′-methyl-N′-phenyl-hydrazino)-propyl]-5-methyl-N′,N′-dipropyl-isophthalamide

Example 2N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[N′-methyl-N′-(4-methyl-pentanoyl)-hydrazino]-propyl}-5-methyl-N′,N′-dipropyl-isophthalamide

Example 3N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-phenoxyamino-propyl]-5-methyl-N′,N′-dipropyl-isophthalamide

BIOLOGICAL EXAMPLES Example A

Enzyme Inhibition Assay

The compounds of the invention are analyzed for inhibitory activity byuse of the MBP-C125 assay. This assay determines the relative inhibitionof beta-secretase cleavage of a model APP substrate, MBP-C125SW, by thecompounds assayed as compared with an untreated control. A detaileddescription of the assay parameters can be found, for example, in U.S.Pat. No. 5,942,400. Briefly, the substrate is a fusion peptide formed ofmaltose binding protein (MBP) and the carboxy terminal 125 amino acidsof APP-SW, the Swedish mutation. The beta-secretase enzyme is derivedfrom human brain tissue as described in Sinha et. al, 1999, Nature40:537-540) or recombinantly produced as the full-length enzyme (aminoacids 1-501), and can be prepared, for example, from 293 cellsexpressing the recombinant cDNA, as described in WO00/47618.

Inhibition of the enzyme is analyzed, for example, by immunoassay of theenzyme's cleavage products. One exemplary ELISA uses an anti-MBP captureantibody that is deposited on precoated and blocked 96-well high bindingplates, followed by incubation with diluted enzyme reaction supernatant,incubation with a specific reporter antibody, for example, biotinylatedanti-SW192 reporter antibody, and further incubation withstreptavidin/alkaline phosphatase. In the assay, cleavage of the intactMBP-C125SW fusion protein results in the generation of a truncatedamino-terminal fragment, exposing a new SW-192 antibody-positive epitopeat the carboxy terminus. Detection is effected by a fluorescentsubstrate signal on cleavage by the phosphatase. ELISA only detectscleavage following Leu 596 at the substrate's APP-SW 751 mutation site.

Specific Assay Procedure:

Compounds are diluted in a 1:1 dilution series to a six-pointconcentration curve (two wells per concentration) in one 96-plate rowper compound tested. Each of the test compounds is prepared in DMSO tomake up a 10 millimolar stock solution. The stock solution is seriallydiluted in DMSO to obtain a final compound concentration of 200micromolar at the high point of a 6-point dilution curve. Ten (10)microliters of each dilution is added to each of two wells on row C of acorresponding V-bottom plate to which 190 microliters of 52 millimolarNaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc diluted compound plateis spun down to pellet precipitant and 20 microliters/well istransferred to a corresponding flat-bottom plate to which 30 microlitersof ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SWsubstrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09%TX100 per 30 microliters) is added. The final reaction mixture of 200micromolar compound at the highest curve point is in 5% DMSO, 20millimolar NaAc, 0.06% TX100, at pH 4.5.

Warming the plates to 37 degrees C. starts the enzyme reaction. After 90minutes at 37 degrees C., 200 microliters/well cold specimen diluent isadded to stop the reaction and 20 microliters/well is transferred to acorresponding anti-MBP antibody coated ELISA plate for capture,containing 80 microliters/well specimen diluent. This reaction isincubated overnight at 4 degrees C. and the ELISA is developed the nextday after a 2 hour incubation with anti-192SW antibody, followed byStreptavidin-AP conjugate and fluorescent substrate. The signal is readon a fluorescent plate reader.

Relative compound inhibition potency is determined by calculating theconcentration of compound that showed a fifty percent reduction indetected signal (IC₅₀) compared to the enzyme reaction signal in thecontrol wells with no added compound. In this assay, the compounds ofthe invention exhibited an IC₅₀ of less than 50 micromolar.

Example B

Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

A synthetic APP substrate that can be cleaved by beta-secretase andhaving N-terminal biotin and made fluorescent by the covalent attachmentof oregon green at the Cys residue is used to assay beta-secretaseactivity in the presence or absence of the inhibitory compounds of theinvention. Useful substrates include the following:Biotin-SEVNL-DAEFR[oregon green]KK [SEQ ID NO:1]Biotin-SEVKM-DAEFR[oregon green]KK [SEQ ID NO:2]Biotin-GLNIKTEEISEISY-EVEFRC[oregon [SEQ ID NO:3] green]KKBiotin-ADRGLTTRPGSGLTNIKTEEISEVNL- [SEQ ID NO:4] DAEF[oregon green]KKBiotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFF [SEQ ID NO:5] YTPKA[oregongreen]KK

The enzyme (0.1 nanomolar) and test compounds (0.001-100 micromolar) areincubated in pre-blocked, low affinity, black plates (384 well) at 37degrees C. for 30 minutes. The reaction is initiated by addition of 150millimolar substrate to a final volume of 30 microliter per well. Thefinal assay conditions are: 0.001-100 micromolar compound inhibitor; 0.1molar sodium acetate (pH 4.5); 150 nanomolar substrate; 0.1 nanomolarsoluble beta-secretase; 0.001% Tween 20, and 2% DMSO. The assay mixtureis incubated for 3 hours at 37 ° C., and the reaction is terminated bythe addition of a saturating concentration of immunopure streptavidin.After incubation with streptavidin at room temperature for 15 minutes,fluorescence polarization is measured, for example, using a LJL Acqurest(Ex485 nm/ Em530 nm). The activity of the beta-secretase enzyme isdetected by changes in the fluorescence polarization that occur when thesubstrate is cleaved by the enzyme. Incubation in the presence orabsence of compound inhibitor demonstrates specific inhibition ofbeta-secretase enzymatic cleavage of its synthetic APP substrate. Inthis assay, compounds of the invention exhibited an IC50 of less than 50micromolar.

Example C

Beta-Secretase Inhibition: P26-P4′SW assay

Synthetic substrates containing the beta-secretase cleavage site of APPare used to assay beta-secretase activity, using the methods described,for example, in published PCT application WO00/47618. The P26-P4′SWsubstrate is a peptide of the sequence:(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL [SEQ ID NO:6] DAEF The P26-P1standard has the sequence: (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL [SEQ IDNO:7]

Briefly, the biotin-coupled synthetic substrates are incubated at aconcentration of from about 0 to about 200 micromolar in this assay.When testing inhibitory compounds, a substrate concentration of about1.0 micromolar is preferred. Test compounds diluted in DMSO are added tothe reaction mixture, with a final DMSO concentration of 5%. Controlsalso contain a final DMSO concentration of 5%. The concentration of betasecretase enzyme in the reaction is varied, to give productconcentrations with the linear range of the ELISA assay, about 125 to2000 picomolar, after dilution.

The reaction mixture also includes 20 millimolar sodium acetate, pH 4.5,0.06% Triton X100, and is incubated at 37 degrees C. for about 1 to 3hours. Samples are then diluted in assay buffer (for example, 145.4nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7millimolar sodium azide, 0.05% Triton X405, 6 g/liter bovine serumalbumin, pH 7.4) to quench the reaction, then diluted further forimmunoassay of the cleavage products.

Cleavage products can be assayed by ELISA. Diluted samples and standardsare incubated in assay plates coated with capture antibody, for example,SW192, for about 24 hours at 4 degrees C. After washing in TTBS buffer(150 millimolar sodium chloride, 25 millimolar Tris, 0.05% Tween 20, pH7.5), the samples are incubated with strepavidin-AP according to themanufacturer's instructions. After a one hour incubation at roomtemperature, the samples are washed in TTBS and incubated withfluorescent substrate solution A (31.2 g/liter2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction withstreptavidin-alkaline phosphate permits detection by fluorescence.Compounds that are effective inhibitors of beta-secretase activitydemonstrate reduced cleavage of the substrate as compared to a control.

Example D

Assays using Synthetic Oligopeptide-Substrates

Synthetic oligopeptides are prepared that incorporate the known cleavagesite of beta-secretase, and optionally detectable tags, such asfluorescent or chouromogenic moieties. Examples of such peptides, aswell as their production and detection methods are described in U.S.Pat. No. 5,942,400, herein incorporated by reference. Cleavage productscan be detected using high performance liquid chouromatography, orfluorescent or chouromogenic detection methods appropriate to thepeptide to be detected, according to methods well known in the art.

By way of example, one such peptide has the sequence SEVNL-DAEF [SEQ IDNO: 8], and the cleavage site is between residues 5 and 6. Anotherpreferred substrate has the sequence ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[SEQ ID NO: 9], and the cleavage site is between residues 26 and 27.

These synthetic APP substrates are incubated in the presence ofbeta-secretase under conditions sufficient to result in beta-secretasemediated cleavage of the substrate. Comparison of the cleavage resultsin the presence of the compound inhibitor to control results provides ameasure of the compound's inhibitory activity.

Example E

Inhibition of Beta-Secretase Activity—Cellular Assay

An exemplary assay for the analysis of inhibition of beta-secretaseactivity utilizes the human embryonic kidney cell line HEKp293 (ATCCAccession No. CRL-1573) transfected with APP751 containing the naturallyoccurring double mutation Lys651Met52 to Asn651Leu652 (numbered forAPP751), commonly called the Swedish mutation and shown to overproduce Abeta (Citron et. al., 1992, Nature 360:672-674), as described in U.S.Pat. No. 5,604,102.

The cells are incubated in the presence/absence of the inhibitorycompound (diluted in DMSO) at the desired concentration, generally up to10 micrograms/ml. At the end of the treatment period, conditioned mediais analyzed for beta-secretase activity, for example, by analysis ofcleavage fragments. A beta can be analyzed by immunoassay, usingspecific detection antibodies. The enzymatic activity is measured in thepresence and absence of the compound inhibitors to demonstrate specificinhibition of beta-secretase mediated cleavage of APP substrate.

Example F

Inhibition of Beta-Secretase in Animal Models of AD

Various animal models can be used to screen for inhibition ofbeta-secretase activity. Examples of animal models useful in theinvention include, but are not limited to, mouse, guinea pig, dog, andthe like. The animals used can be wild type, transgenic, or knockoutmodels. In addition, mammalian models can express mutations in APP, suchas APP695-SW and the like described herein. Examples of transgenicnon-human mammalian models are described in U.S. Pat. Nos. 5,604,102,5,912,410 and 5,811,633.

PDAPP mice, prepared as described in Games et.al., 1995, Nature373:523-527 are useful to analyze in vivo suppression of A beta releasein the presence of putative inhibitory compounds. As described in U.S.Pat. No. 6,191,166, 4 month old PDAPP mice are administered compoundformulated in vehicle, such as corn oil. The mice are dosed withcompound (1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10hours, the animals are sacrificed, and brains removed for analysis.

Transgenic animals are administered an amount of the compound inhibitorformulated in a carrier suitable for the chosen mode of administration.Control animals are untreated, treated with vehicle, or treated with aninactive compound. Administration can be acute, i.e., single dose ormultiple doses in one day, or can be chouronic, i.e., dosing is repeateddaily for a period of days. Beginning at time 0, brain tissue orcerebral fluid is obtained from selected animals and analyzed for thepresence of APP cleavage peptides, including A beta, for example, byimmunoassay using specific antibodies for A beta detection. At the endof the test period, animals are sacrificed and brain tissue or cerebralfluid is analyzed for the presence of A beta and/or beta-amyloidplaques. The tissue is also analyzed for necrosis.

Animals administered the compound inhibitors of the invention areexpected to demonstrate reduced A beta in brain tissues or cerebralfluids and reduced beta amyloid plaques in brain tissue, as comparedwith non-treated controls.

Example G

Inhibition of A Beta Production in Human Patients

Patients suffering from Alzheimer's Disease (AD) demonstrate anincreased amount of A beta in the brain. AD patients are administered anamount of the compound inhibitor formulated in a carrier suitable forthe chosen mode of administration. Administration is repeated daily forthe duration of the test period. Beginning on day 0, cognitive andmemory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; A beta depositsin the brain; amyloid plaque in the brain; and scores for cognitive andmemory function, as compared with control, non-treated patients.

Example H

Prevention of A Beta Production in Patients at Risk for AD

Patients predisposed or at risk for developing AD are identified eitherby recognition of a familial inheritance pattern, for example, presenceof the Swedish Mutation, and/or by monitoring diagnostic parameters.Patients identified as predisposed or at risk for developing AD areadministered an amount of the compound inhibitor formulated in a carriersuitable for the chosen mode of administration. Administration isrepeated daily for the duration of the test period. Beginning on day 0,cognitive and memory tests are performed, for exmple, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; amyloid plaque inthe brain; and scores for cognitive and memory function, as comparedwith control, non-treated patients.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

Unless defined otherwise, all scientific and technical terms used hereinhave the same meaning as commonly understood by one of skill in the artto which this invention belongs.

All patents and publications referred to herein are hereby incorporatedby reference for all purposes.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1-30. (canceled)
 31. A protected compound of the formula (II)

where R₁ is: (I) C₁-C₆ alkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁-C₃ alkyl,C₁-C₇ alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃ alkoxy),—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, and—OC═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,(II) —CH₂—S(O)₀₋₂—(C₁-C₆ alkyl), (III) —CH₂—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),(IV) C₂-C₆ alkenyl with one or two double bonds, optionally substitutedwith one, two or three substituents selected from the group consistingof —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (V) C₂-C₆ alkynyl withone or two triple bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are —H or C₁-C₆ alkyl, (VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero orone and where R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl,indenyl, dihydronaphthalyl, or tetralinyl optionally substituted withone, two, three or four of the following substituents on the aryl ring:(A) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, and C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above, (B) C₂-C₆ alkenyl withone or two double bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are —H or C₁-C₆ alkyl, (C) C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (D)—F, Cl, —Br or —I, (F) —C₁-C₆ alkoxy optionally substituted with one,two or three of —F, (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) areas defined below, (H) —OH, (I) —C≡N, (J) C₃-C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (K)—CO—(C₁-C₄ alkyl), (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, or (N) —SO₂—(C₁-C₄ alkyl), (VII)—(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined above and whereR_(1-heteroaryl) is selected from the group consisting of: pyridinyl,pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,pyrazinyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl,indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl,thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl,cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl,tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl,pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl dihydroquinolinyl dihydroquinolinonyldihydroisoquinolinonyl dihydrocoumarinyl dihydroisocoumarinylisoindolinonyl benzodioxanyl benzoxazolinonyl pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide, where theR_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by any ring atom of theparent R_(1-heteroaryl) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is optionally substituted with one, two, three orfour of: (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (2) C₂-C₆ alkenyl with one ortwo double bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are —H or C₁-C₆ alkyl, (3) C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (4)—F, Cl, —Br or —I, (6) —C₁-C₆ alkoxy optionally substituted with one,two, or three of —F, (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) areas defined below, (8) —OH, (9) —C≡N, (10) C₃-C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (11)—CO—(C₁-C₄ alkyl), (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, or (14) —SO₂—(C₁-C₄ alkyl), with the proviso thatwhen n₁ is zero R_(1-heteroaryl) is not bonded to the carbon chain bynitrogen; or (VIII) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is asdefined above and R_(1-heterocycle) is selected from the groupconsisting of: morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,tetrahydrothienyl, homopiperidinyl, homomorpholinyl,homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,where the R_(1-heterocycle) group is bonded by any atom of the parentR_(1-heterocycle) group substituted by hydrogen such that the new bondto the R_(1-heterocycle) group replaces the hydrogen atom and its bond,where heterocycle is optionally substituted with one, two, three orfour: (1) C₁-C₆ alkyl optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (2) C₂-C₆ alkenyl with one ortwo double bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are —H or C₁-C₆ alkyl, (3) C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (4)—F, Cl, —Br or —I, (5) C₁-C₆ alkoxy, (6) —C₁-C₆ alkoxy optionallysubstituted with one, two, or three —F, (7) —NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) are as defined below, (8) —OH, (9) —C≡N, (10) C₃-C₇cycloalkyl, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H orC₁-C₆ alkyl, (11) —CO—(C₁-C₄ alkyl), (12) —SO₂—NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (13) —CO—NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (14) —SO₂—(C₁-C₄ alkyl), or(15) ═O, with the proviso that when n₁ is zero R_(1-heterocycle) is notbonded to the carbon chain by nitrogen; where R₂ is: (I) —H, (II) C₁-C₆alkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are as defined above, (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ isR_(1-aryl) or R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) areas defined above; (IV) C₂-C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (V)C₂-C₆ alkynyl with one or two triple bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, or (VI) —(CH₂)₀₋₄—C₃-C₇cycloalkyl, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H orC₁-C₆ alkyl; where R₃ is: (I) —H, (II) C₁-C₆ alkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl)where R_(1-aryl) and R_(1-heteroaryl) are as defined above (IV) C₂-C₆alkenyl with one or two double bonds, (V) C₂-C₆ alkynyl with one or twotriple bonds; or (VI) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substitutedwith one, two or three substituents selected from the group consistingof —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b)where R_(1-a)and R_(1-b) are —H or C₁-C₆ alkyl, and where R₂ and R₃ aretaken together with the carbon to which they are attached to form acarbocycle of three, four, five, six, or seven carbon atoms, optionallywhere one carbon atom is replaced by a heteroatom selected from thegroup consisting of —O—, —S—, —SO₂—, and —NR_(N-2)—, where R_(N-2) isselected from the group consisting of: (a) —H, (b) —C₁-C₆ alkyloptionally substituted with one substitutent selected from the groupconsisting of: (i) —OH, and (ii) —NH₂, (c) —C₁-C₆ alkyl optionallysubstituted with one, two, or three —F, —Cl, —Br, or —I, (d) —C₃-C₇cycloalkyl, (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (f) —(C₁-C₆alkyl)-O—(C₁-C₃ alkyl), (g) —C₂-C₆ alkenyl with one or two double bonds,(h) —C₂-C₆ alkynyl with one or two triple bonds, (i) —C₁-C₆ alkyl chainwith one double bond and one triple bond, (j) —R_(1-aryl) whereR_(1-aryl) is as defined above, and (k) —R_(1-heteroaryl) whereR_(1-heteroaryl) is as defined above; where R_(N) is: (I) R_(N-1)—X_(N)—where X_(N) is selected from the group consisting of: (A) —CO—, (B)—SO₂—, (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and are—H and C₁-C₄ alkyl, (D) —CO—(CR′R″)₁₋₆—X_(N-1) where X_(N-1) is selectedfrom the group consisting of —O—, —S— and —NR′— and where R′ and R″ areas defined above, and (E) a single bond; where R_(N-1) is selected fromthe group consisting of: (A) R_(N-aryl) where R_(N-aryl) is phenyl,1-naphthyl, 2-naphthyl, tetralinyl, indanyl,6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, or dihydronaphthyloptionally substituted with one, two or three of the followingsubstituents which can be the same or different and are: (1) C₁-C₆alkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are as defined above, (2) —OH, (3) —NO₂, (4) —F, —Cl, —Br,—I, (5) —CO—OH, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2)and R_(N-3) are the same or different and are selected from the groupconsisting of: (a) —H, (b) —C₁-C₆ alkyl optionally substituted with onesubstitutent selected from the group consisting of: (i) —OH, and (ii)—NH₂, (C) —C₁-C₆ alkyl optionally substituted with one, two, or three—F, —Cl, —Br, or —I, (d) —C₃-C₇ cycloalkyl, (e) —(C₁-C₂ alkyl)-(C₃-C₇cycloalkyl), (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), (g) —C₂-C₆ alkenyl withone or two double bonds, (h) —C₂-C₆ alkynyl with one or two triplebonds, (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,(j) —R_(1-aryl) where R_(1-aryl) is as defined above, and (k)—R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (8)—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one,two or three double bonds), (10) —(CH₂)₀₋₄—CO— (C₂-C₁₂ alkynyl with one,two or three triple bonds), (11) —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), (12)—(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined above, (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove, (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(—1-heterocycle) isas defined above, (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selectedfrom the group consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof C₁-C₆ alkyl, (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selectedfrom the group consisting of: (a) C₁-C₆ alkyl, (b)—(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above, (c) C₂-C₆alkenyl containing one or two double bonds, (d) C₂-C₆ alkynyl containingone or two triple bonds, (e) C₃-C₇ cycloalkyl, and (f)—(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl) is as defined above,(17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined above, (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO_(2—)(C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5) )—CO—O—R_(N-5) where R_(N-5) can be thesame or different and is as defined above, (22) —(CH₂)₀₋₄—N (H orR_(N-5))—CO—N(R_(N-5))₂, where R_(N-5) can be the same or different andis as defined above, (23) —(CH₂)₀₋₄—N—CS—N (R_(N-5))₂, where R_(N-5) canbe the same or different and is as defined above, (24) —(CH₂)₀₋₄—N(—H orR_(N-5))—CO—R_(N-2) where R_(N-5) and R_(N-2) can be the same ordifferent and are as defined above, (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) can be the same or different and are as definedabove, (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above, (27)—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂where R_(N-aryl-1) is —H or C₁-C₄ alkyl, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂where R_(N-5) is as defined above, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ whereR_(N-5) is as defined above, (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5)is as defined above, (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) isas defined above, (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is asdefined above, (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted withone, two, three, four, or five of —F), (35) C₃-C₇ cycloalkyl, (36) C₂-C₆alkenyl with one or two double bonds optionally substituted with C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (37)C₂-C₆ alkynyl with one or two triple bonds optionally substituted withC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (38)—(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) and R_(N-2) can bethe same of different and are as described above, or (39)—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (B) —R_(N-heteroaryl) where R_(N-heteroaryl)is selected from the group consisting of: pyridinyl, pyrimidinyl,quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl,isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl,indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl,thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl,cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl,tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl,pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide where theR_(N-heteroaryl) group is bonded by any atom of the parentR_(N-heteroaryl) group substituted by hydrogen such that the new bond tothe R_(N-heteroaryl) group replaces the hydrogen atom and its bond,where heteroaryl is optionally substituted with one, two, three, or fourof: (1) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (2) —OH, (3) —NO₂, (4) —F,—Cl, —Br, or —I, (5) —CO—OH, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or different and are selectedfrom the group consisting of: (a) —H, (b) —C₁-C₆ alkyl optionallysubstituted with one substitutent selected from the group consisting of:(i) —OH, and (ii) —NH₂, (c) —C₁-C₆ alkyl optionally substituted withone, two, or three —F, —Cl, —Br, —I, (d) —C₃-C₇ cycloalkyl, (e) —(C₁-C₂alkyl)-(C₃-C₇ cycloalkyl), (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), (g)—C₂-C₆ alkenyl with one or two double bonds, (h) —C₂-C₆ alkynyl with oneor two triple bonds, (i) —C₁-C₆ alkyl chain with one double bond and onetriple bond, (j) —R_(1-aryl) where R_(1-aryl) is as defined above, (k)—R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (8)—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), (9) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl with one,two or three double bonds), (10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one,two or three triple bonds), (11) —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl), (12)—(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined above, (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove, (14) —(CH₂)₀₋₄—CO-R_(1-heterocycle) where R_(—1-heterocycle) isas defined above, (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selectedfrom the group consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof C₁-C₆ alkyl, (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selectedfrom the group consisting of: (a) C₁-C₆ alkyl, (b)—(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above, (c) C₂-C₆alkenyl containing one or two double bonds, (d) C₂-C₆ alkynyl containingone or two triple bonds, (e) C₃-C₇ cycloalkyl, and (f)—(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl) is as defined above,(17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined above, (18) —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂₋(C₁-C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be thesame or different and is as defined above, (22) —(CH₂)₀₋₄—N(H orR_(N-5))—CO—N (R_(N-5))₂, where R_(N-5) can be the same or different andis as defined above, (23) —(CH₂)₀₋₄—N—CS—N (R_(N-5))₂, where R_(N-5) canbe the same or different and is as defined above, (24) —(CH₂)₀₋₄—N(—H orR_(N-5))—CO—R_(N-2) where R_(N-5) and R_(N-2) can be the same ordifferent and are as defined above, (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) can be the same or different and are as definedabove, (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above, (27)—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂where R_(N-aryl-1) is —H or C₁-C₄ alkyl, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂where R_(N-5) is as defined above, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ whereR_(N-5) is as defined above, (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5)is as defined above, (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) isas defined above, (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is asdefined above, (34) —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted withone, two, three, four, or five of —F), (35) C₃-C₇ cycloalkyl, (36) C₂-C₆alkenyl with one or two double bonds optionally substituted with C₁-C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (37)C₂-C₆ alkynyl with one or two triple bonds optionally substituted withC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (38)—(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) and R_(N-2) can bethe same of different and are as defined above, or (39) —(CH₂)₀₋₄—C₃-C₇cycloalkyl, (C) R_(N-aryl)—W—R_(N-aryl), where R_(N-aryl) can be thesame or different, (D) R_(N-aryl)—W—R_(N-heteroaryl), (E)R_(N-aryl)—W—R_(N-1-heterocycle), wherein R_(N-1-heterocycle) is thesame as R_(1-heterocycle), and R_(1-heterocycle) is as defined above (F)R_(N-heteroaryl)—W—R_(N-aryl), (G) R_(N-heteroaryl)—W—R_(N-heteroaryl),(H) R_(N-heteroaryl)—W—R_(N-1-heterocycle), (I)R_(N-heterocycle)—W—R_(N-aryl), wherein R_(N-heterocycle) is the same asR_(1-heterocycle), and R_(1-heterocycle) is as defined above, andR_(N-aryl) is as defined above, (J)R_(N-heterocycle)—W—R_(N-heteroaryl), and (K)R_(N-heterocycle)—W—R_(N-1-heterocycle), where W is (1) —(CH₂)₀₋₄—, (2)—O—, (3) —S(O)₀₋₂—, (4) —N(R_(N-5))— where R_(N-5) is as defined above,or (5) —CO—; (II) —CO—(C₁-C₁₀ alkyl) where alkyl is optionallysubstituted with one three substitutents selected from the groupconsisting of: (A) —OH, (B) —C₁-C₆ alkoxy, (C) —C₁-C₆ thioalkoxy, (D)—CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or -phenyl, (E)—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or differentand are as defined above, (F) —CO—R_(N-4) where R_(N-4) is as definedabove, (G) —SO₂—(C₁-C₈ alkyl), (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2)and R_(N-3) are the same or different and are as defined above, (I)—NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8) where R_(N-8) is as definedabove, (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above, (L) —R_(N-4) where R_(N-4) is asdefined above, (M) —O—CO—(C₁-C₆ alkyl), (N) —O—CO—NR_(N-8)R_(N-8) whereR_(N-8) are the same or different and are as defined above, (O)—O—(C₁-C₅ alkyl)-COOH, (P) —O—(C₁-C₆ alkyl optionally substitued withone, two, or three of —F, —CI, —Br, or —I), (Q) —NH—SO₂—(C₁-C₆ alkyl),and (R) —F, or —Cl, (III) —CO—(C₁-C₆ alkyl)—O—(C₁-C₆ alkyl) where alkylis optionally substituted with one, two, or three substitutents selectedfrom the group consisting of: (A) —OH, (B) —C₁-C₆ alkoxy, (C) —C₁-C₆thioalkoxy, (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or-phenyl, (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are as defined above, (F) —CO—R_(N-4) where R_(N-4) isas defined above, (G) —SO₂—(C₁-C₈ alkyl), (H) —SO₂—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) are the same or different and are as defined above,(I) —NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8) where R_(N-8) is asdefined above, (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are thesame or different and are as defined above, (L) —R_(N-4) where R_(N-4)is as defined above, (M) —O—CO—(C₁-C₆ alkyl), (N) —O—CO—NR_(N-8)R_(N-8)where R_(N-8) are the same or different and are as defined above, (O)—O—(C₁-C₅ alkyl)-COOH, (P) —O—(C₁-C₆ alkyl optionally substitued withone, two, or three of —F, —CI, —Br, or —I), (Q) —NH—SO₂—(C₁-C₆ alkyl),and (R) —F, or —Cl, (IV) —CO—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl) where alkylis optionally substituted with one, two, or three of substitutentsselected from the group consisting of: (A) —OH, (B) —C₁-C₆ alkoxy, (C)—C₁-C₆ thioalkoxy, (D) —CO—O—R_(N-8) where R_(N-8) is as defined above,(E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above, (F) —CO—R_(N-4) where R_(N-4) is asdefined above, (G) —SO₂—(C₁-C₈ alkyl), (H) —SO₂—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) are the same or different and are as defined above,(I) —NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8) where R_(N-8) is asdefined above, (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are thesame or different and are as defined above, (L) —R_(N-4) where R_(N-4)is as defined above, (M) —O—CO—(C₁-C₆ alkyl), (N) —O—CO—NR_(N-8)R_(N-8)where R_(N-8) are the same or different and are as defined above, (O)—O—(C₁-C₅ alkyl)-COOH, (P) —O—(C₁-C₆ alkyl optionally substitued withone, two, or three of —F, —Cl, —Br, or —I), (Q) —NH—SO₂—(C₁-C₆ alkyl),and (R) —F, or —Cl, (V)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl)) whereR_(N-aryl) and R_(N-heteroaryl) are as defined above, where R_(N-10) isselected from the group consisting of: (A) —H, (B) C₁-C₆ alkyl, (C)C₃-C₇ cycloalkyl, (D) C₂-C₆ alkenyl with one double bond, (E) C₂-C₆alkynyl with one triple bond, (F) R_(1-aryl) where R_(1-aryl) is asdefined above, and (G) R_(N-heteroaryl) where R_(N-heteroaryl) is asdefined above, or (VI) —CO—(C₃-C₈ cycloalkyl) where alkyl is optionallysubstituted with one or two substitutents selected from the groupconsisting of: (A) —(CH₂)₀₋₄—OH, (B) —(CH₂)₀₋₄—C₁-C₆ alkoxy, (C)—(CH₂)₀₋₄—C₁-C₆ thioalkoxy, (D) —(CH₂)₀₋₄—CO—O—R_(N-8) where R_(N-8) is—H, C₁-C₆ alkyl or phenyl, (E) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) are the same or different and are as defined above,(F) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is as defined above, (G)—(CH₂)₀₋₄—SO₂—(C₁-C₈ alkyl), (H) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) are the same or different and are as defined above,(I) —(CH₂)₀₋₄—NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8) where R_(N-8) isas defined above, (K) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) andR_(N-3) are the same or different and are as defined above, (L)—(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above, (M) —O—CO—(C₁-C₆alkyl), (N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same ordifferent and are as defined above, (O) —O—(C₁-C₅ alkyl)-COOH, (P)—O—(C₁-C₆ alkyl optionally substitued with one, two, or three of —F,—Cl, —Br, or —I), (Q) —NH—SO₂—(C₁-C₆ alkyl), and (R) —F, or —Cl; whereR_(A) is: (I) —C₁-C₁₀ alkyl optionally substituted with one, two orthree substituents selected from the group consisting of C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, —OC═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,—S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above, —NR_(1-a)C═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, —C═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, and—S(═O)₂ NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,(II) —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkyl can be optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkCyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃,C₁-C₆ alkoxy, —O-phenyl, —CO—OH, —CO—O—(C₁-C₄ alkyl), and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (III)—(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl) where R_(A-x) and R_(A-y) are (A) —H,(B) C₁-C₄ alkyl optionally substituted with one or two —OH, (C) C₁-C₄alkoxy optionally substituted with one, two, or three of —F, (D)—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (E) C₂-C₆ alkenyl containing one or twodouble bonds, (F) C₂-C₆ alkynyl contianing one or two triple bonds, or(G) phenyl, and where R_(A-x) and R_(A-y) are taken together with thecarbon to which they are attached to form a carbocycle of three, four,five, six or seven carbon atoms, optionally where one carbon atom isreplaced by a heteroatom selected from the group consisting of —O—, —S—,—SO₂—, and —NR_(N-2)— and R_(A-aryl) is the same as R_(N-aryl), (IV)—(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl) where R_(A-heteroaryl) is thesame as R_(N-heteroaryl) and R_(A-x) and R_(A-y) are as defined above,(V) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)-R_(A-aryl) where R_(A-aryl),R_(A-x) and R_(A-y) are as defined above, (VI)—(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)-R_(A-heteroaryl) where R_(A-aryl)R_(A-heteroaryl), R_(A-x) and R_(A-y) are as defined above, (VII)—(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)-R_(A-aryl) whereR_(A-heteroaryl), R_(A-aryl), R_(A-x) and R_(A-y) are as defined above,(VIII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)-R_(A-heteroaryl) whereR_(A-heteroaryl), R_(A-x) and R_(A-y) are as defined above, (IX)—(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl)-R_(A-heterocycle) whereR_(A-heterocycle) is defined as R_(1-heterocycle), and where R_(A-aryl),R_(A-x) and R_(A-y) are as defined above, (X)—(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl)-R_(A-heterocycle) whereR_(A-heteroaryl), R_(A-heterocycle), R_(A-x) and R_(A-y) are as definedabove, (XI) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)-R_(A-aryl) whereR_(A-heterocycle), R_(A-aryl), R_(A-x) and R_(A-y) are as defined above,(XII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)-R_(A-heteroaryl) whereR_(A-heterocycle), R_(A-heteroaryl), R_(A-x) and R_(A-y) are as definedabove, (XIII) —(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle)-R_(A-heterocycle)where R_(A-heterocycle), R_(A-x) and R_(A-y) are as defined above, (XIV)—(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle) where R_(A-heterocycle), R_(A-x)and R_(A-y) are as defined above, (XV)—[C(R_(A-1))(R_(A-2))]₁₋₃—CO—N—(R_(A-3))₂ where R_(A-1) and R_(A-2) arethe same or different and are selected from the group consisting of: (A)—H, (B) —C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (C)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy,—O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (D) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (E) —(CH₂)₁₋₂—S (O)₀₋₂—(C₁-C₆ alkyl), (F) —(CH₂)₀₋₄—C₃-C₇cycloalkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above, (G) —(C₁-C₄alkyl)-R_(A′-aryl) where R_(A′-aryl) is as defined for R_(1-aryl), (H)—(C₁-C₄ alkyl)-R_(A-heteroaryl) where R_(A-heteroaryl) is as definedabove, (I) —(C₁-C₄ alkyl)-R_(A-heterocycle) where R_(A-heterocycle) isas defined above, (J) —R_(A-heteroaryl w)here R_(A-heteroaryl) is asdefined above, (K) —R_(A-heterocycle) where R_(A-heterocycle) is asdefined above, (M) —(CH₂)₁₋₄—R_(A-4)—(CH₂)₀₋₄—R_(A′-aryl) where R_(A-4)is —O—, —S— or —NR_(A-5)— where R_(A-5) is C₁-C₆ alkyl, and whereR_(A′-aryl) is defined above, (N)—(CH₂)₁₋₄—R_(A-4)—(CH₂)₀₋₄—R_(A-heteroaryl) where R_(A-4) andR_(A-heteroaryl) are as defined above, and (O) —R_(A′-aryl) whereR_(A′-aryl) is as defined above, and where R_(A-3) is the same ordifferent and is: (A) —H, (B) —C₁-C₆ alkyl optionally substituted withone, two or three substituents selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy,—O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (C) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (D) C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (E) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (F) —R_(A′-aryl) where R_(A′-aryl) is as defined above,(G) —R_(A-heteroaryl) where R_(A-heteroaryl) is as defined above, (H)—R_(A-heterocycle) where R_(A-heterocycle) is as defined above, (I)—(C₁-C₄ alkyl)-R_(A′-aryl) where R_(A′-aryl) is as defined above, (J)—(C₁-C₄ alkyl)-R_(A-heteroaryl) where R_(A-heteroaryl) is as definedabove, (K) —(C₁-C₄ alkyl)-R_(A-heterocycle) where R_(A-heterocycle) isas defined above, or (XVI) —CH(R_(A-aryl))₂ where R_(A-aryl) are thesame or different and are as defined above, (XVII)—CH(R_(A-heteroaryl))₂ where R_(A-heteroaryl) are the same or differentand are as defined above, (XVIII) —CH(R_(A-aryl))(R_(A-heteroaryl))where R_(A-aryl) and R_(A-heteroaryl) are as defined above, (XIX)-cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to R_(A-aryl),R_(A-heteroaryl), R_(A-heterocycle) where R_(A-aryl) or R_(A-heteroaryl)or R_(A-heterocycle) are as defined above where one carbon ofcyclopentyl, cyclohexyl, or -cycloheptyl is optionally replaced with NH,NR_(N-5), O, or S(═O)₀₋₂, and where cyclopentyl, cyclohexyl, or-cycloheptyl can be optionally substituted with one or two —C₁-C₃ alkyl,—F, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, ═O, or —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (XX) C₂-C₁₀ alkenyl containingone or two double bonds optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (XXI)C₂-C₁₀ alkynyl containing one or two triple bonds optionally substitutedwith one, two or three substituents selected from the group consistingof C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy,—O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (XXI) —(CH₂)₀₋₁—CHR_(A-6)—(CH₂)₀₋₁—R_(A-aryl) where R_(A-aryl) isas defined above and R_(A-6) is —(CH₂)₀₋₆—OH, (XXII)—(CH₂)₀₋₁—CHR_(A-6)—(CH₂)₀₋₁—R_(A-heteroaryl) where R_(A-heteroaryl) andR_(A-6) is as defined above, (XXIII) —CH(—R_(A-aryl) orR_(A-heteroaryl))-CO—O (C₁-C₄ alkyl) where R_(A-aryl) andR_(A-heteroaryl) are as defined above, (XXIV)—CH(—CH₂—OH)—CH(—OH)-micro-NO₂, (XXV) (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)—OH,(XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂, (XXVIII) —H, (XXIX)—(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and R_(1-b) are asdefined above; or (XXX) —C═OC(HR₆)NHR₇, where R₆ and R₇ are as definedbelow, —C═OR₇, where R₇ is as defined below, —C═OOR₇, where R₇ is asdefined below, or —SOOR₇ where R₇ is as defined below, wherein R₆ is:hydrogen, C₁-C₃ alkyl, phenyl, thioalkoxyalkyl, alkyl substituted aryl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,haloalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminoalkyl,(N-protected)aminoalkyl, alkylaminoalkyl,((N-protected)(alkyl)amino)alkyl, dialkylaminoalkyl, guanidinoalkyl,lower alkenyl, heterocyclic, (heterocyclic)alkyl), arylthioalkyl,arylsulfonyalkyl, (heterocyclic)thioalkyl, (heterocyclic)sulfonylalkyl,(heterocyclic)oxyalkyl, arylalkoxyalkyl, arylthioalkoxyalkyl,arylalkylsulfonylalkyl, (heterocyclic))alkoxyalkyl,(heterocyclic)thioalkoxyalkyl, (heterocyclic)alkylsulfonylalkyl,cycloalkyloxyalkyl, cycloalkylthioalkyl, cycloalkylsulfonylalkyl,cycloalkylalkoxyalkyl, cycloalkylthioalkoxyalkyl,cycloalkylalkylsulfonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aroylalkyl, (heterocyclic)carbonylalkyl,polyhydroxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, aryloxyalkyl, or alkylsulfonylalkyl, whereinheterocyclic is pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,furanyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl andtetrahydro[2H]pyranyl and wherein the heterocycle is unsubstituted orsubstituted with one to three substituents independently selected fromhydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, COOH, —SO₃H,lower alkenyl or lower alkyl; wherein R₇ is: C₁-C₃ alkyl, phenyl,thioalkoxyalkyl, (aryl)alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl,alkoxyalkyl, aryloxyalkyl, haloalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminoalkyl, (N-protected)aminocalkyl, alkylaminoalkyl,((N-protected)(alkyl)amino)alkyl, dialkylaminoalkyl, guanidinoalkyl,lower alkenyl, heterocyclic, (heterocyclic)alkyl), arylthioalkyl,arylsulfonyalkyl, (heterocyclic)thioalkyl, (heterocyclic)sulfonylalkyl,(heterocyclic)oxyalkyl, arylalkoxyalkyl, arylthioalkoxyalkyl,arylalkylsulfonylalkyl, (heterocyclic))alkoxyalkyl,(heterocyclic)thioalkoxyalkyl, (heterocyclic)alkylsulfonylalkyl,cycloalkyloxyalkyl, cycloalkylthioalkyl, cycloalkylsulfonylalkyl,cycloalkylalkoxyalkyl, cycloalkylthioalkoxyalkyl,cycloalkylalkylsulfonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aroylalkyl, (heterocyclic)carbonylalkyl,polyhydroxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, aryloxyalkyl, or alkylsulfonylalkyl, whereinheterocyclic is pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,furanyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl andtetrahydro[2H]pyranyl and wherein the heterocycle is unsubstituted orsubstituted with one to three substituents independently selected fromhydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, COOH, —SO₃H,lower alkenyl or lower alkyl; where R_(B) is: (I) —C₁-C₁₀ alkyloptionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, —OC═O NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is asdefined above, —NR_(1-a)C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, —C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, and —S(═O)₂ NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, (II) —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl where cycloalkylcan be optionally substituted with one, two or three. substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, —CO—OH, —CO—O—(C₁-C₄alkyl), and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (III) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl) where R_(B-x) and R_(B-y)are (A) —H, (B) C₁-C₄ alkyl optionally substituted with one or two —OH,(C) C₁-C₄ alkoxy optionally substituted with one, two, or three of —F,(D) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (E) C₂-C₆ alkenyl containing one or twodouble bonds, (F) C₂-C₆ alkynyl contianing one or two triple bonds, or(G) phenyl, and where R_(B-x) and R_(B-y) are taken together with thecarbon to which they are attached to form a carbocycle of three, four,five, six or seven carbon atoms, optionally where one carbon atom isreplaced by a heteroatom selected from the group consisting of —O—, —S—,—SO₂—, and —NR_(N-2) where R_(N-2) is as defined above, and R_(B-aryl)is the same as R_(N-aryl) and is defined above (IV)—(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl) where R_(B-heteroaryl) is thesame as R_(N-heteroaryl), R_(B-x), and R_(B-y) are as defined above, (V)—(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)-R_(B-aryl) where R_(B-aryl), R_(B-x),and R_(B-y) are as defined above, (VI)—(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)-R_(B-heteroaryl) where R_(B-aryl),R_(B-heteroaryl), R_(B-x) and R_(B-y) are as defined above, (VII)—(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl)-R_(B-aryl) whereR_(B-heteroaryl), R_(B-aryl), R_(B-x) and R_(B-y) are as defined above,(VIII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl)-R_(B-heteroaryl) whereR_(B-heteroaryl), R_(B-x) and R_(B-y) are as defined above, (IX)—(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl)-R_(B-heterocycle) whereR_(B-heterocycle) is defined as R_(1-heterocycle), and where R_(B-aryl),R_(B-x) and R_(B-y) are as defined above, (X)—(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl)-R_(B-heterocycle) whereR_(B-heteroaryl), R_(B-heterocycle), R_(B-x) and R_(B-y) are as definedabove, (XI) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)-R_(B-aryl) whereR_(B-heterocycle), R_(B-aryl), R_(B-x) and R_(B-y) are as defined above,(XII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)-R_(B-heteroaryl) whereR_(B-heterocycle), R_(B-heteroaryl), R_(B-x) and R_(B-y) are as definedabove, (XIII) —(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle)-R_(B-heterocycle)where R_(B-heterocycle), R_(B-x) and R_(B-y) are as defined above, (XIV)—(CR_(B-x) R_(B-y))₀₋₄—R_(B-heterocycle) where R_(B-heterocycle),R_(B-x) and R_(B-y) are as defined above, (XV) —[C(R_(B-1))(R_(B-2))]₁₋₃—CO—N—(R_(B-3))₂ where R_(B-1) and R_(B-2) are the same ordifferent and are selected from the group consisting of: (A) —H, (B)—C₁-C₆ alkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b)where Rlia and R_(1-b) are as defined above, (C) C₂-C₆ alkenyl with oneor two double bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (D)C₂-C₆ alkynyl with one or two triple bonds, optionally substituted withone, two or three substituents selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy,—O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), (F) —(CH₂)₀₋₄—C₃-C₇cycloalkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above, (G) —(C₁-C₄alkyl)-R_(B′-aryl) where R_(B′-aryl) is as defined above for R_(1-aryl),(H) —(C₁-C₄ alkyl)-R_(B-heteroaryl) where R_(B-heteroaryl) is as definedabove, (I) —(C₁-C₄ alkyl)-R_(B-heterocycle) where R_(B-heterocycle) isas defined above, (J) —R_(B-heteroaryl) where R_(B-heteroaryl) is asdefined above, (K) —R_(B-heterocycle) where R_(B-heterocycle) is asdefined above, (M) —(CH₂)₁₋₄—R_(B-4)—(CH₂)₀₋₄—R_(B′-aryl) where R_(B-4)is —O—, —S— or —NR_(B-5)— where R_(B-5) is C₁-C₆ alkyl, and whereR_(B′-aryl) is defined above, (N)—(CH₂)₁₋₄—R_(B-4)—(CH₂)₀₋₄—R_(B-heteroaryl) where R_(B-4) andR_(B-heteroaryl) are as defined above, and (O) —R_(B′-aryl) whereR_(B′-aryl) is as defined above, and where R_(B-3) is the same ordifferent and is: (A) —H, (B) —C₁-C₆ alkyl optionally substituted withone, two or three substituents selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy,—O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (C) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (D) C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (E) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (F) —R_(B′-aryl) where R_(B′-aryl) is as defined above,(G) —R_(B-heteroaryl) where R_(B-heteroaryl) is as defined above, (H)—R_(B-heterocycle) where R_(B-heterocycle) is as defined above, (I)—(C₁-C₄ alkyl)-R_(B′-aryl) where R_(B′-aryl) is as defined above, (J)—(C₁-C₄ alkyl)-R_(B-heteroaryl) where R_(B-heteroaryl) is as definedabove, (K) —(C₁-C₄ alkyl)-R_(B-heterocycle) where R_(B-heterocycle) isas defined above, or (XVI) —CH(R_(B-aryl))₂ where R_(B-aryl) are thesame or different and are as defined above, (XVII)—CH(R_(B-heteroaryl))₂ where R_(B-heteroaryl) are the same or differentand are as defined above, (XVIII) —CH(R_(B-aryl)) (R_(B-heteroaryl))where R_(B-aryl) and R_(B-heteroaryl) are as defined above, (XIX)-cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to R_(B-aryl) orR_(B-heteroaryl) or R_(B-heterocycle) where pt R_(B-aryl) orR_(B-heteroaryl) or R_(B-heterocycle) are as defined above where onecarbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionallyreplaced with NH, NR_(N-5), O, or S(═O)₀₋₂, and where cyclopentyl,cyclohexyl, or -cycloheptyl can be optionally substituted with one ortwo —C₁-C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, ═O, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (XX)C₂-C₁₀ alkenyl containing one or two double bonds optionally substitutedwith one, two or three substituents selected from the group consistingof C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy,—O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (XXI) C₂-C₁₀ alkynyl containing one or two triple bondsoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₆ alkoxy, —O-phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (XXI)—(CH₂)₀₋₁—CHR_(c-6)—(CH₂)₀₋₁—RB_(B-aryl) where R_(B-aryl) is as definedabove and R_(c-6) is —(CH₂)₀₋₆—OH, (XXII)—(CH₂)₀₋₁—CHR_(B-6)—(CH₂)₀₋₁—R_(B-heteroaryl) where R_(B-heteroaryl) andR_(c-6) is as defined above, (XXIII) —CH(—R_(B-aryl) orR_(B-heteroaryl))—CO—O (C₁-C₄ alkyl) where R_(B-aryl) andR_(B-heteroaryl) are as defined above, (XXIV)—CH(—CH₂—OH)—CH(—OH)-micro-NO₂, (XXV) (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)—OH,(XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂, (XXVIII) —H, or (XXIX)—(CH₂)₀₋₆—C(═NR_(1-a)) (NR_(1-a)R_(1-b)) where R_(1-a) and R_(1-b) areas defined above; and where PROTECTING GROUP is selected from the groupconsisting of t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl,acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl,difluoroacetyl, fluoroacetyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluorenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H.
 32. A protected compoundaccording to claim 31 where R₁ is: —(CH₂)₀₋₁—(R_(1-aryl)), or(CH₂)_(n1)—(R_(1-heteroaryl)); where R_(N) is: R_(N-1)—X_(N)—, whereX_(N) is selected from the group consisting of: —CO—, and —SO₂—, whereR_(N-1) is selected from the group consisting of: —R_(N-aryl), and—R_(N-heteroaryl), or —CO—CH(—(CH₂)₀₋₂—O—R_(N-)₁₋₁₀)—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl)); where R_(A) is: —C₁-C₈alkyl, (CH₂)₀₋₃—(C₃-C₇) cycloalkyl, (CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl),(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl),(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle), cyclopentyl or -cyclohexyl ringfused to R_(A-aryl) or R_(A-heteroaryl) or R_(A-heterocycle); whereR_(B) is: —C₁-C₈ alkyl, —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl,—(CR_(A-x)R_(A-y))₀₋₄—R_(A-aryl),—(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl),—(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle), -cyclopentyl or -cyclohexylring fused to R_(A-aryl) or R_(A-heteroaryl) or R_(A-heterocycle).
 33. Aprotected compound according to claim 31 where R₁ is:—(CH₂)—(R_(1-aryl)), or —(CH₂)—(R_(1-heteroaryl)); where R₂ is —H;.where R₃ is —H; where R_(N) is: R_(N-1)—X_(N)— where X_(N) is: —CO—,where R_(N-1) is selected from the group consisting of: —R_(N-aryl), and—R_(N-heteroaryl); where R_(A) is: —C₁-C₈ alkyl, —(CH₂)₀₋₃—(C₃-C₇)cycloalkyl, —(CR_(A-x)R_(A-y))₀₋₄-R_(A-aryl),—(CR_(A-x)R_(A-y))₀₋₄—R_(A-heteroaryl),—(CR_(A-x)R_(A-y))₀₋₄—R_(A-heterocycle), or -cyclopentyl or -cyclohexylring fused to R_(A-aryl) or R_(A-heteroaryl) or R_(A-heterocycle); whereR_(B) is: —C₁-C₈ alkyl, —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl,—(CR_(B-x)R_(B-y))₀₋₄—R_(B-aryl), or—(CR_(B-x)R_(B-y))₀₋₄—R_(B-heteroaryl).—(CR_(B-x)R_(B-y))₀₋₄—R_(B-heterocycle), -cyclopentyl or -cyclohexylring fused to R_(B-aryl) or R_(B-heteroaryl) or R_(B-heterocycle).
 34. Aprotected compound according to claim 31 where PROTECTING GROUP ist-butoxycarbonyl.
 35. A protected compound according to claim 31 wherePROTECTING GROUP is benzyloxycarbonyl. 36-147. (canceled)